CN1411435A - Novel use of phenyl hetero alkylamine derivatives - Google Patents

Novel use of phenyl hetero alkylamine derivatives Download PDF

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Publication number
CN1411435A
CN1411435A CN01805489A CN01805489A CN1411435A CN 1411435 A CN1411435 A CN 1411435A CN 01805489 A CN01805489 A CN 01805489A CN 01805489 A CN01805489 A CN 01805489A CN 1411435 A CN1411435 A CN 1411435A
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benzonitrile
chloro
amino
oxygen base
compound
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CN01805489A
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CN1235870C (en
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D·彻希雷
S·康诺利
D·科西
P·哈姆利
A·米特
A·皮姆
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AstraZeneca AB
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AstraZeneca AB
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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Abstract

There is disclosed the use of a compound of formula (I) wherein R<1>, R<2>, X, Y, V, W and Z are as defined in the specification, and pharmaceutically acceptable salts, enantiomers or racemates thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial. Certain novel compounds of formula (Ia) and pharmaceutically acceptable salts thereof, and enantiomers and racemates thereof are disclosed; together with processes for their preparation, compositions containing them and their use in therapy. The compounds of formulae (I) and (Ia) are inhibitors of the enzyme nitric oxide synthase and are thereby particularly useful in the treatment or prophylaxis of inflammatory disease.

Description

The new application of phenyl hetero alkylamine derivatives
Invention field
The present invention relates to the application of phenyl hetero alkylamine derivatives as the enzyme nitric oxide synthase inhibitors.The invention also discloses some new phenyl hetero alkylamine derivatives and preparation method thereof, contain their composition and the application in treatment thereof.
Background of invention
In mammalian cell, the effect by specific nitricoxide synthase (NOS) produces nitrogen protoxide by the L-arginine.These enzymes belong to two different classes of-composing type NOS (cNOS) and induced NOS (iNOS).Two kinds of composing type NOS and a kind of induced NOS have been identified at present.As if in the middle of composing type NOS, endothelium enzyme (ecNOS) relates to the regulation and control of smooth muscle loosening and blood pressure and blood flow, and neurone enzyme (ncNOS) plays neurotransmitter, and relate to for example regulation and control of cerebral ischemia of multiple biological function.Shown that induced NOS is particularly related to the pathogeny of inflammatory diseases.Therefore, the regulation and control of these enzymes should have the very big multiple disease of treatment possibility (J.E.Macdonald, Ann.Rep.Med.Chem., 1996,31,221-230).
People have paid the compound of the specific inhibitor of one or more isoforms that a lot of effort determine to can be used as the enzyme nitricoxide synthase.The application of such compound in treatment is also claimed in patent widely.
Patent application EP0 273 658 discloses following formula: compound
Figure A0180548900111
Wherein the Ar representative is optional by halogen, C1-4 alkyl, C1-3 alkoxyl group or CF 3The phenyl that replaces, or the optional naphthyl that replaces; R 1Represent thienyl, furyl, pyridyl or the thiazolyl of C5-7 cycloalkyl, thienyl, halogenated thiophene base, (C1-4 alkyl)-replacement; And R 2And R 3Be H or methyl independently respectively.Described compound is the effective selectivity inhibitor of thrombotonin and norepinephrine uptake, so the applicant claims that it can be used for treating human diseases for example anxiety disorder, dysthymia disorders and obesity.
U.S. patent 4,314, and 081 discloses following formula: compound Wherein the Ar representative is optional by the phenyl of halogen, C1-4 alkyl, C1-3 alkoxyl group or the replacement of C3-4 alkenyl; Perhaps Ar represents naphthyl; And R 1, R 2And R 3Be H or methyl independently respectively.Described compound is the effective selectivity inhibitor of thrombotonin and norepinephrine uptake, so the applicant claims that it can be used for treating human diseases for example dysthymia disorders and obesity.
Patent application WO92/19210 discloses following formula: compound
Figure A0180548900122
Ar wherein 1And Ar 2The phenyl that is replaced by different substituents is chosen in representative wantonly independently, and condition is Ar 1And Ar 2In the middle of have at least one to be replaced by at least one halogen atom; And R 1And R 2Be H or C1-4 alkyl independently respectively.The applicant claims that described compound can be used for the neurotransmitter re-uptake system in the imaging brain.
Patent application DE29 07 217 discloses following formula: compound
Figure A0180548900123
Ar wherein 1The phenyl that representative is replaced by nitro, optional Cl, Br, the CF of being selected from of described phenyl 3, Me or OMe another substituting group replace; Ar 2Representative is optional by the phenyl of Cl, Br or F replacement; R 1Represent H or C1-5 alkyl; And R 2Represent the C1-5 alkyl.The applicant claims that these compounds can be used for treating eating disorder and dysthymia disorders.
Patent application GB2 060 620 discloses following formula: compound
Figure A0180548900131
Ar wherein 1Representative is optional by C1-6 alkyl, C2-6 alkenyl, CF 3, the phenyl that replaces of halogen, nitro, amino or acyl amino; The Ar representative is selected from C1-6 alkyl, C1-6 alkoxyl group, CF by at least one 3, the phenyl that replaces of nitro or amino group; R 1, R 2And R 4Represent H or C1-6 alkyl independently; And R 3Represent H, C1-6 alkyl or benzyl.The applicant claims that these compounds can be used as antidepressive.
Patent application GB2 060 621 discloses following formula: compound Wherein the Ar representative is optional by the phenyl of C1-6 alkyl or halogen replacement; Ar 1Representative is by NO 2, the phenyl that replaces of amino or acyl amino; R 1And R 2Represent H or C1-6 alkyl independently.The applicant claims that these compounds can be used as antidepressive.
Patent application EP318 727 discloses following formula: compound R wherein 1Can represent the optional alkyl or cycloalkyl that replaces, and R 2Can represent the optional phenyl that replaces.These compounds stop the calcium overload in the brain cell, and therefore can be used for treating anoxia, migraine, local asphyxia and epilepsy.
Patent application EP399 504 discloses following formula: compound Wherein the phenyl that replaces is chosen in the Ar representative wantonly; R can represent the optional phenyl that replaces; And R 1And R 2Can represent the optional alkyl or cycloalkyl that replaces.These compounds stop the calcium overload in the brain cell, and therefore can be used for treating anoxia, migraine, local asphyxia and epilepsy.
Patent application EP576 766 discloses following formula: compound
Figure A0180548900141
Wherein the phenyl that replaces is chosen in the Ar representative wantonly; R can represent the optional phenyl that replaces; And R 1And R 2Can represent the optional alkyl or cycloalkyl that replaces; Perhaps group NR 1R 2The first ring of the optional substituted 5-7 of representative.These compounds stop the calcium overload in the brain cell, and therefore can be used for treating anoxia, traumatic injury, neurodegenerative disease, migraine, local asphyxia and epilepsy.
Patent application EP571 685 discloses the compound that is similar to EP576 766, but wherein furyl, thienyl or the pyrryl that replaces chosen in the Ar representative wantonly.
The present invention relates to following wonderful discovery, i.e. one group of phenyl hetero alkylamine derivatives, some compound that is included in the general range of some above-mentioned background technical publicationss is the inhibitor of enzyme nitricoxide synthase.
Summary of the invention
The invention provides formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification Wherein: X and Y represent C1-4 alkyl, C1-4 alkoxyl group, halogen, CF independently 3, OCF 3, CN, C ≡ CH, S (O) mCH 3, S (O) pCF 3, NO 2Or NHCHO; M and p represent integer 0,1 or 2 independently; Z represents hydrogen or fluorine; V represents O; W represents phenyl or contains 1-3 the heteroatomic 5 or 6 yuan of fragrant heterocycles that are independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by one or more halogen, C1-4 alkyl, C1-4 alkoxyl group, OH, CN, NO of being independently selected from 2Or NR 4R 5Substituting group replace; Described alkyl or alkoxyl group can be chosen wantonly by one or more fluorine atoms and replace; R 1And R 2Represent H, C1-4 alkyl or C3-6 cycloalkyl independently; Described alkyl is optional to be replaced by following groups: C1-4 alkoxyl group, halogen, hydroxyl, NR 6R 7, phenyl or contain heteroatomic 5 or 6 yuan of aromatics or the saturated heterocyclic that 1-3 is independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by halogen, C1-4 alkyl, C1-4 alkoxyl group, CF 3, OCF 3, CN or NO 2Replace; Perhaps group NR 1R 2Representative is optional together also comprises one and is selected from O, S or NR 8The saturated nitrogen heterocyclic of other heteroatomic 4-8 unit; Described ring is optional to be replaced by C1-4 alkyl, C1-4 alkoxyl group or OH; Described alkyl is optional by C1-4 alkoxyl group, OH or NR 9R 10Replace; Perhaps group NR 1R 2The part of 5 yuan of aromatics nitrogen heterocyclics that also comprise an other N atom is chosen in representative wantonly together; R 4, R 5, R 6, R 7, R 9And R 10Represent H or C1-4 alkyl independently; R 8Represent H or C1-6 alkyl; Described alkyl is optional to be replaced by following groups: C1-4 alkoxyl group, OH, NR 11R 12, phenyl or contain heteroatomic 5 or 6 yuan of aromatics or the saturated heterocyclic that 1-3 is independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by halogen, C1-4 alkyl, C1-4 alkoxyl group, CF 3, OCF 3, CN or NO 2Replace; R 11And R 12Represent H or C1-4 alkyl independently; Be used for the treatment of or prevent to benefit from application in the medicine of repressed disease of nitric oxide synthase activity or illness in preparation.
In yet another aspect, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification is used for the treatment of or prevents to benefit from nitricoxide synthase and induce application in the medicine of the disease of isoform activity inhibited or illness in preparation.
More specific aspect of the present invention provides formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification to be used for the treatment of or to prevent application in the medicine of inflammatory diseases in preparation.
The present invention also provides and has treated the method that can benefit from repressed disease of nitric oxide synthase activity or illness or reduce the danger of described disease or illness, comprises to suffering from or dangerous formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or the racemic modification of suffering from people's administering therapeutic significant quantity of described disease or illness.
In addition, the present invention also provides treatment can benefit from the method that nitricoxide synthase is induced the disease or the illness of isoform activity inhibited or reduced the danger of described disease or illness, comprises to suffering from or dangerous formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or the racemic modification of suffering from people's administering therapeutic significant quantity of described disease or illness.
More particularly, the present invention also provide suffer from or the dangerous people who suffers from inflammatory diseases in treatment inflammatory diseases or reduce the method for inflammatory diseases danger, described method comprises formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or the racemic modification to described people's administering therapeutic significant quantity.
In yet another aspect, the invention provides and be used for the treatment of or prevent to benefit from the disease that nitric oxide synthase activity suppresses or the pharmaceutical preparation of illness, wherein comprise formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or the racemic modification for the treatment of significant quantity and with the pharmaceutically acceptable auxiliary agent of its blended, diluent or carrier.
Another preferred aspect, the invention provides and be used for the treatment of or prevent to benefit from the pharmaceutical preparation that nitricoxide synthase is induced the disease or the illness of isoform activity inhibited, wherein comprise formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or the racemic modification for the treatment of significant quantity and with the pharmaceutically acceptable auxiliary agent of its blended, diluent or carrier.
Another more special aspect, the invention provides the pharmaceutical preparation that is used for the treatment of or prevents inflammatory diseases, wherein comprise formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or the racemic modification for the treatment of significant quantity and with the pharmaceutically acceptable auxiliary agent of its blended, diluent or carrier.
For the purpose of favourable, formula (I) compound can also be united use with another kind of pharmaceutically active substance, particularly induces isoform (COX-2) inhibitor to unite use with cyclo-oxygenase.Therefore, in yet another aspect, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification and combine with cox 2 inhibitor in the application of treatment in inflammation, inflammatory diseases or the inflammatory relative disease.The present invention also provides to suffering from or dangerously suffering from human therapy inflammation, inflammatory diseases and the inflammatory relative disease of described disease or illness or reduce its dangerous method, comprises formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification and cox 2 inhibitor to the co-administered treatment significant quantity of described people.
In a preferred embodiment, X and Y represent Br, Cl, CH independently 3, CF 3Or CN.X especially preferably represents Br, Cl or CF 3Y especially preferably represents Cl or CN.
W preferably represents and contains 1-3 5 or 6 yuan of fragrant heterocycles that are independently selected from the heteroatomic optional replacement of O, S and N.Particularly preferred example is that wherein W represents those of thienyl, furyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl or pyrimidyl.
R 1And R 2The preferred H or optional that represents independently by the C1-4 alkyl of C1-4 alkoxyl group or hydroxyl replacement.R 1And R 2More preferably represent H or methyl independently.
The application of following formula (I) compound and pharmacologically acceptable salt, enantiomorph or racemic modification is included in the scope of the present invention clearly: 2-(3-amino-1-phenyl propoxy-)-4-benzyl chloride nitrile; 4-chloro-2-(3-(methylamino)-1-phenyl propoxy-) benzonitrile; 4-bromo-2-[(1R)-and 3-(methylamino)-1-phenyl propoxy-] benzonitrile; γ-R-(2-bromo-5-chlorophenoxy)-Corvitin; 4-chloro-2-{[(1R)-and 3-chloro-1-phenyl propyl] the oxygen base } benzonitrile; 4-methoxyl group-2-[3-(methylamino)-1-phenyl amino-1-phenyl propoxy-] benzonitrile; The 4-methyl-2-{[(1R)-3-(methylamino)-1-phenyl propyl] the oxygen base } benzonitrile; R-γ-(2, the 5-dichlorophenoxy)-N-methyl-2-thiophene propylamine; S-γ-(2, the 5-dichlorophenoxy)-N-methyl-2-thiophene propylamine; 2-[[(3R)-and 3-(2, the 5-dichlorophenoxy)-3-(2-thienyl) propyl group] amino] ethanol; 4-chloro-2-{[(1R)-and 3-(4-methyl isophthalic acid-piperazinyl)-1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-and 3-(4-hydroxyl-piperidino)-1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-and the 3-[(2-hydroxyethyl) methylamino]-the 1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-and 3-(4-morpholinyl)-1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-3-[(3R)-3-hydroxyl pyrrolidine base]-the 1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-3-[(3S)-3-hydroxyl pyrrolidine base]-the 1-phenyl propyl] the oxygen base }-benzonitrile; 2-{[(1R)-and 3-amino-1-phenyl propyl] the oxygen base }-5-fluoro-4-methyl benzonitrile; 4-chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidyl) propoxy-] benzonitrile; 4-chloro-5-fluoro-2-((1R)-and 1-(3-furyl)-3-[(2-methoxy ethyl) amino] propyl group } the oxygen base) benzonitrile; The 4-methoxyl group-2-[[(1R)-3-(methylamino)-1-phenyl propyl] the oxygen base]-benzonitrile; γ-(2-bromo-5-fluorophenoxy)-N-methyl-amphetamine; (R)-γ-(5-bromo-2-chlorophenoxy)-Corvitin; (R)-γ-(2-bromo-5-nitro-phenoxy)-Corvitin; 4-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-methoxy ethyl) amino]-the 1-phenyl propyl] the oxygen base]-benzonitrile; 4-chloro-2-{[(1R)-and 3-(cyclopropyl amino)-1-phenyl propyl] the oxygen base }-5-fluorine benzonitrile; 4-chloro-2-{[(1R)-and 3-(cyclopropyl amino)-1-(3-furyl) propyl group] the oxygen base }-5-fluorine benzonitrile; 4-chloro-2-{[(1R)-and 3-(cyclopropyl amino)-1-(3-thienyl) propyl group] the oxygen base }-5-fluorine benzonitrile; 4-bromo-2-{[(1R)-and 3-(cyclopropyl amino)-1-(phenyl) propyl group] the oxygen base }-5-fluorine benzonitrile; 4-bromo-2-{[(1R)-and 3-(cyclopropyl amino)-1-(3-furyl) propyl group] the oxygen base }-5-fluorine benzonitrile; 4-bromo-2-{[(1R)-and 3-(cyclopropyl amino)-1-(3-thienyl) propyl group] the oxygen base }-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-((1R)-and the 3-[(3-hydroxypropyl) amino]-the 1-phenyl propyl } the oxygen base) benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 1-(3-furyl)-3-(3-hydroxypropyl) amino] propyl group] the oxygen base } benzonitrile; 4-chloro-5-fluoro-2-{[(1R)-and the 3-[(3-hydroxypropyl) amino]-1-(3-thienyl) propyl group] the oxygen base) benzonitrile; 4-bromo-5-fluoro-2-((1R)-and the 3-[(3-hydroxypropyl) amino]-the 1-phenyl propyl } the oxygen base) benzonitrile; 4-bromo-5-fluoro-2-((1R)-and 1-(3-furyl)-3-[(3-hydroxypropyl) amino] propyl group } the oxygen base) benzonitrile; 4-bromo-5-fluoro-2-{[(1R)-and the 3-[(3-hydroxypropyl) amino]-1-(3-thienyl) propyl group] the oxygen base } benzonitrile; 2-[[(1R)-and 3-amino-1-phenyl propyl] the oxygen base]-4-(trifluoromethyl) benzonitrile; 2-[[(1R)-and 3-amino-1-phenyl propyl] the oxygen base]-4-benzyl chloride nitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-(methylamino)-1-phenyl propyl] the oxygen base] benzonitrile; 2-[[(1R)-and 3-amino-1-phenyl propyl] the oxygen base]-4-chloro-5-fluorine benzonitrile; γ-[5-chloro-2-(trifluoromethyl) phenoxy group]-Corvitin; 2-[[(1R)-and 3-(methylamino)-1-phenyl propyl] the oxygen base]-4-(trifluoromethyl) benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[(5-methylpyrazine base) methyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[(1H-imidazoles-2-ylmethyl) amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-2-[[(1R)-and 3-[[2-(dimethylamino) ethyl] amino]-the 1-phenyl propyl] the oxygen base]-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(4-morpholinyl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(1H-imidazoles-1-yl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(1H-imidazol-4 yl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 2-[[(1R)-and the 3-[(2-amino-ethyl) amino]-the 1-phenyl propyl] the oxygen base]-4-chloro-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 1-phenyl-3-[(3,3, the 3-trifluoro propyl) amino] propyl group] the oxygen base] benzonitrile; 2-{[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base }-4-benzyl chloride nitrile; 4-chloro-2-{[(1R)-and 3-(methylamino)-1-(2-thiazolyl) propyl group] the oxygen base } benzonitrile; (R)-γ-(2, the 5-dichlorophenoxy)-2-thiazole propylamine; 2-[3-amino-1-(2-oxazolyl) propoxy-]-4-benzyl chloride nitrile; γ-(2, the 5-dichlorophenoxy)-2-oxazole propylamine; 2-[[-3-amino-1-(3-pyridyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridyl) propoxy-] benzonitrile; γ-[2-chloro-5-(trifluoromethyl) phenoxy group]-3-pyridine propylamine; 2-[3-amino-1-(6-methoxyl group-2-pyridyl) propoxy-]-4-chloro-5-fluorine benzonitrile; 2-[3-amino-1-(1,6-dihydro-6-oxo-2-pyridyl) propoxy-]-4-chloro-5-fluorine benzonitrile; 2-[3-amino-1-(6-bromo-3-pyridyl) propoxy-]-4-benzyl chloride nitrile; 2-[[3-amino-1-(5-isoxazolyl) propyl group] the oxygen base]-4-benzyl chloride nitrile; 4-chloro-2-[3-[(2-hydroxyethyl) amino]-1-(5-isoxazolyl) propoxy-] benzonitrile; (R)-γ-(2, the 5-dichlorophenoxy)-5-isoxazole propylamine; (R)-γ-(2, the 5-dichlorophenoxy)-N-methyl-amphetamine; (R)-γ-[2-chloro-5-(trifluoromethyl) phenoxy group]-N-methyl-amphetamine; 4-chloro-2-[[(1R)-and 3-(methylamino)-1-(2-thienyl) propyl group] the oxygen base] benzonitrile; 2-[[(1R)-and 3-amino-1-(3-furyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 1-(3-furyl)-3-methylamino) propyl group] the oxygen base]-benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-(methylamino)-1-(3-thienyl) propyl group] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-1-(3-thienyl) propyl group] the oxygen base] benzonitrile; 2-[[(1R)-and the 3-[(2-amino-ethyl) amino]-1-(3-thienyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; 2-[[(1R)-and 3-amino-1-(3-thienyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile; 4-chloro-2-[3-(methylamino)-1-(2-thiazolyl) propoxy-]-benzonitrile; 2-[[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; γ-(2-chloro-5-nitro-phenoxy)-Corvitin; (R)-and γ-(5-chloro-2-nitro-phenoxy)-N-methylbenzene) propylamine; 4-chloro-5-fluoro-2-{ (1R)-3-[(2-fluoro ethyl) amino]-the 1-phenyl propyl] the oxygen base } benzonitrile; 2-[[(1R)-and 3-amino-1-phenyl propyl] the oxygen base]-4-bromo-5-fluorine benzonitrile; 3-[[(3R)-and 3-(2, the 5-dichlorophenoxy)-3-phenyl propyl] amino]-the 1-propyl alcohol; 1-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-the 4-piperidine carbinols; N-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-the 2-thiophene methyl amine; N-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-5-methyl-2-furylamine; 4-chloro-2-[[(1R)-and 1-phenyl-3-(1-piperazinyl) propyl group] the oxygen base] benzonitrile; 5-fluoro-2-[[(1 R)-and the 3-[(2-hydroxyethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base]-4-methyl benzonitrile; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-5-fluoro-4-methyl-benzonitrile; 4-chloro-2-[[(1R)-and 3-[(1, the 1-dimethyl ethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base] benzonitrile; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-benzonitrile; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; (R)-γ-(2, the 5-dichlorophenoxy)-3-isoxazole propylamine; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-(trifluoromethyl)-benzonitrile; (R)-γ-[2-chloro-5-(trifluoromethyl) phenoxy group]-2-pyridine propylamine; 2-[[(1R)-and 3-amino-1-(5-methyl-3-isoxazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile.
In this article, except as otherwise noted, otherwise term " C1-4 alkyl " is meant the straight or branched alkyl with 1-4 carbon atom.Such examples of groups comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.
Similar explanation should be done in term " C1-6 alkyl ".
In this article, except as otherwise noted, otherwise term " C3-6 cycloalkyl " is meant the cycloalkyl with 3-6 carbon atom.Such examples of groups comprises cyclopropyl, cyclopentyl and cyclohexyl.
In this article, except as otherwise noted, otherwise term " C1-4 alkoxyl group " is meant the straight or branched alkoxyl group with 1-4 carbon atom.Such examples of groups comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy and tert.-butoxy.
The example of " optional C1-4 alkyl or the C1-4 alkoxyl group that is replaced by one or more fluorine atoms " comprises CF 3, CF 3CF 2, CF 3CH 2, CH 2FCH 2, CH 3CF 2, CF 3CH 2CH 2, OCF 3And OCH 2CF 3
In this article, except as otherwise noted, otherwise term " halogen " is meant fluorine, chlorine, bromine and iodine.
Optional also comprise an example that is selected from the other saturated nitrogen heterocyclic of heteroatomic 4-8 unit of O, S or N and comprise tetramethyleneimine, piperidines, piperazine, morpholine and perhydro azepine.
Contain 1-3 the heteroatomic 5 or 6 yuan of fragrant heterocyclic examples that are independently selected from O, S and N and comprise furans, thiophene, pyridine, thiazole, imidazoles, oxazole, triazole, oxadiazole, thiadiazoles and pyrimidine.
Contain 1-3 example that is independently selected from heteroatomic 5 or 6 yuan of saturated heterocyclics of O, S and N and comprise tetramethyleneimine, tetrahydrofuran (THF), piperidines and piperazine.
The optional example that also comprises 5 yuan of aromatics nitrogen heterocyclics of an other N atom comprises pyrroles and imidazoles.
Some formulas (I) compound is new.Therefore, the present invention provides formula (Ia) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification on the other hand Wherein: X and Y represent C1-4 alkyl, C1-4 alkoxyl group, halogen, CF independently 3, OCF 3, CN, C ≡ CH, S (O) mCH 3, S (O) pCF 3, NO 2Or NHCHO; M and p represent integer 0,1 or 2 independently; Z represents hydrogen or fluorine; V represents O; W represents phenyl or contains 1-3 the heteroatomic 5 or 6 yuan of fragrant heterocycles that are independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by one or more halogen, C1-4 alkyl, C1-4 alkoxyl group, OH, CN, NO of being independently selected from 2Or NR 4R 5Substituting group replace; Described alkyl or alkoxyl group can be chosen wantonly by one or more fluorine atoms and replace; R 1And R 2Represent H, C1-4 alkyl or C3-6 cycloalkyl independently; Described alkyl is optional to be replaced by following groups: C1-4 alkoxyl group, halogen, hydroxyl, NR 6R 7, phenyl or contain heteroatomic 5 or 6 yuan of aromatics or the saturated heterocyclic that 1-3 is independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by halogen, C1-4 alkyl, C1-4 alkoxyl group, CF 3, OCF 3, CN or NO 2Replace; Perhaps group NR 1R 2Representative is optional together also comprises one and is selected from O, S or NR 8The saturated nitrogen heterocyclic of other heteroatomic 4-8 unit; Described ring is optional to be replaced by OH or C1-4 alkyl, and described alkyl is by C1-4 alkoxyl group, OH or NR 9R 10Replace; Perhaps group NR 1R 2The part of 5 yuan of aromatics nitrogen heterocyclics that also comprise an other N atom is chosen in representative wantonly together; R 4, R 5, R 6, R 7, R 9And R 10Represent H or C1-4 alkyl independently; R 8Represent H or C1-6 alkyl; Described alkyl is optional to be replaced by following groups: C1-4 alkoxyl group, OH, NR 11R 12, phenyl or contain heteroatomic 5 or 6 yuan of aromatics or the saturated heterocyclic that 1-3 is independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by halogen, C1-4 alkyl, C1-4 alkoxyl group, CF 3, OCF 3, CN or NO 2Replace; R 11And R 12Represent H or C1-4 alkyl independently; Condition is: when optional phenyl, thienyl, furyl or the pyrryl that replaces of W representative; And R 1Represent H, C1-4 alkyl or C3-6 cycloalkyl, wherein said group is optional when being replaced by the C1-4 alkoxyl group, R 2Do not represent H, C1-4 alkyl or C3-6 cycloalkyl, wherein said group is optional to be replaced by the C1-4 alkoxyl group; With condition be: when W represented thiazolyl or pyridyl, Z represented F; Perhaps have one in the middle of X and the Y at least and represent CN; Perhaps R 1And R 2Dependently represent H or CH 3
In yet another aspect, the present invention relates to formula (Ia) compound, wherein X, Y, V, W, Z, R 1And R 2As defined above, condition is: work as R 1When being H, R 2Not H, C1-4 alkyl or benzyl; With condition be: work as R 1Represent C1-4 alkyl or C3-6 cycloalkyl, wherein said group is optional when being replaced by the C1-4 alkoxyl group, R 2Do not represent C1-4 alkyl or C3-6 cycloalkyl, wherein said group is optional to be replaced by the C1-4 alkoxyl group.
In a preferred embodiment, X and the Y in the formula (Ia) represents Br, Cl, CH independently 3, CF 3Or CN.X especially preferably represents Br, Cl or CF 3Y especially preferably represents Cl or CN.
W in the formula (Ia) preferably represents and contains 1-3 5 or 6 yuan of fragrant heterocycles that are independently selected from the heteroatomic optional replacement of O, S and N.Particularly preferred example is that wherein W represents those of thienyl, furyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl or pyrimidyl.
R in the formula (Ia) 1And R 2The preferred H or optional that represents independently by the C1-4 alkyl of C1-4 alkoxyl group or hydroxyl replacement.R 1And R 2More preferably represent H or methyl independently.
Particularly preferred formula (Ia) compound comprises: 2-[[(3R)-3-(2, the 5-dichlorophenoxy)-3-(2-thienyl) propyl group] amino] ethanol; 4-chloro-2-{[(1R)-and 3-(4-hydroxyl-piperidino)-1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-and the 3-[(2-hydroxyethyl) methylamino]-the 1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-3-[(3R)-3-hydroxyl pyrrolidine base]-the 1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-3-[(3S)-3-hydroxyl pyrrolidine base]-the 1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidyl) propoxy-] benzonitrile; 4-chloro-5-fluoro-2-((1R)-and the 3-[(3-hydroxypropyl) amino]-the 1-phenyl propyl } the oxygen base) benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 1-(3-furyl)-3-(3-hydroxypropyl) amino] propyl group] the oxygen base } benzonitrile; 4-chloro-5-fluoro-2-{[(1R)-and the 3-[(3-hydroxypropyl) amino]-1-(3-thienyl) propyl group] the oxygen base } benzonitrile; 4-bromo-5-fluoro-2-((1R)-and the 3-[(3-hydroxypropyl) amino]-the 1-phenyl propyl } the oxygen base) benzonitrile; 4-bromo-5-fluoro-2-((1R)-and 1-(3-furyl)-3-[(3-hydroxypropyl) amino] propyl group } the oxygen base) benzonitrile; 4-bromo-5-fluoro-2-[[(1R)-and the 3-[(3-hydroxypropyl) amino]-1-(3-thienyl) propyl group] the oxygen base } benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[(5-methylpyrazine base) methyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[(1H-imidazoles-2-ylmethyl) amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-2-[[(1R)-and 3-[[2-(dimethylamino) ethyl] amino]-the 1-phenyl propyl] the oxygen base]-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(4-morpholinyl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(1H-imidazoles-1-yl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(1H-imidazol-4 yl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 2-[[(1R)-and the 3-[(2-amino-ethyl) amino]-the 1-phenyl propyl] the oxygen base]-4-chloro-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 1-phenyl-3-[(3,3, the 3-trifluoro propyl) amino] propyl group] the oxygen base] benzonitrile; 2-{[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base }-4-benzyl chloride nitrile; 4-chloro-2-{[(1R)-and 3-(methylamino)-1-(2-thiazolyl) propyl group] the oxygen base } benzonitrile; 2-[3-amino-1-(2-oxazolyl) propoxy-]-4-benzyl chloride nitrile; γ-(2, the 5-dichlorophenoxy)-2-oxazole propylamine; 2-[[3-amino-1-(3-pyridyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridyl) propoxy-] benzonitrile; 2-[3-amino-1-(6-methoxyl group-2-pyridyl) propoxy-]-4-chloro-5-fluorine benzonitrile; 2-[3-amino-1-(1,6-dihydro-6-oxo-2-pyridyl) propoxy-]-4-chloro-5-fluorine benzonitrile; 2-[3-amino-1-(6-bromo-3-pyridyl) propoxy-]-4-benzyl chloride nitrile; 2-[[3-amino-1-(5-isoxazolyl) propyl group] the oxygen base]-4-benzyl chloride nitrile; 4-chloro-2-[3-[(2-hydroxyethyl) amino]-1-(5-isoxazolyl) propoxy-] benzonitrile; (R)-γ-(2, the 5-dichlorophenoxy)-5-isoxazole propylamine; 4-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-1-(3-thienyl) propyl group] the oxygen base] benzonitrile; 2-[[(1R)-and the 3-[(2-amino-ethyl) amino]-1-(3-thienyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; 4-chloro-2-[3-(methylamino)-1-(2-thiazolyl) propoxy-]-benzonitrile; 2-[[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; 4-chloro-5-fluoro-2-{[(1R)-and the 3-[(2-fluoro ethyl) amino]-the 1-phenyl propyl] the oxygen base } benzonitrile; 3-[[(3R)-and 3-(2, the 5-dichlorophenoxy)-3-phenyl propyl] amino]-the 1-propyl alcohol; 1-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-the 4-piperidine carbinols; N-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-the 2-thiophene methyl amine; N-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-5-methyl-2-furylamine; 5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base]-4-methyl benzonitrile; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-5-fluoro-4-methyl-benzonitrile; 4-chloro-2-[[(1R)-and 3-[(1, the 1-dimethyl ethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base] benzonitrile; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-benzonitrile; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; (R)-γ-(2, the 5-dichlorophenoxy)-3-isoxazole propylamine; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-(trifluoromethyl)-benzonitrile; 2-[[(1R)-and 3-amino-1-(5-methyl-3-isoxazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; With their pharmacologically acceptable salt, enantiomorph or racemic modification.
The present invention also provides formula (Ia) compound or pharmaceutically acceptable salt thereof, enantiomorph or the racemic modification as medicine.
The present invention also provides the method for preparation formula (Ia) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification, and described method comprises: (a) with formula (II) compound
Figure A0180548900261
Wherein X, Y, V and Z react with formula (III) compound suc as formula defining in (Ia)
Figure A0180548900262
Wherein W, R 1And R 2Suc as formula defining in (Ia); Perhaps (b) is with formula (IV) compound
Figure A0180548900263
Wherein X, Y and Z define suc as formula (Ia) is middle, and L 1Be leavings group, react with the formula V compound
Figure A0180548900264
R wherein 1, R 2, V and W be suc as formula defining in (Ia); Perhaps (c) is with formula (VI) compound Wherein X, Y, V, W and Z define suc as formula (Ia) is middle, and L 2Be leavings group, react with formula (VII) compound
HNR 1R 2(VII) R wherein 1And R 2Suc as formula defining in (Ia); Perhaps (d) is with formula (II) compound Wherein X, Y, V and Z react with formula (VIII) compound suc as formula defining in (Ia) R wherein 1, R 2Define suc as formula (Ia) is middle with W, and L 3It is leavings group; Perhaps (e) reduces formula (IX) compound Wherein X, Y, V, W and Z define suc as formula (Ia) is middle, and the G representative changes into NR by going back proper energy 1R 2Group; When needing gained formula (Ia) compound or its another kind of salt are changed into its pharmacologically acceptable salt; Perhaps gained formula (Ia) compound is changed into other formula (Ia) compound; And gained formula (Ia) compound is changed into its optically active isomer when needing.
In method (a), for example use the Mitsunobu condition inert solvent for example in the tetrahydrofuran (THF) with reactant (II) with (III) be coupled together.Therefore, for example, under suitable temperature, usually under the boiling temperature of 0 ℃-solvent, with phosphine-derivatives and azo derivative processing reaction thing.Suitable phosphine-derivatives comprises triphenylphosphine and tributylphosphine.Suitable azo derivative comprise diethyl azodiformate, diisopropyl azodiformate and 1,1 '-(azo dicarbapentaborane) two piperidines.
In method (b), reaction is undertaken by handle the formula V nucleophilic reagent with formula (IV) electrophilic reagent in inert solvent.Suitable leavings group L 1Comprise halide ions, particularly fluoride ion.This reaction is generally for example carried out in the presence of the sodium hydride at non-nucleophilic base.Appropriate organic solvent is for example N-N-methyl-2-2-pyrrolidone N-, tetrahydrofuran (THF), the pure and mild methyl-sulphoxide of C1-4.This reaction is generally carried out under the boiling temperature of 0 ℃-solvent.
Another selection, in method (b), reaction be to use suitable palladium source for example acid chloride (II) for example carry out in the presence of the BINAP at suitable phosphine part.
In method (c), amination reaction is by carrying out (VI) compound and formula (VII) amine in inert solvent.Suitable leavings group L 2Comprise sulfonate radical, trifluoro sulfonate radical, tosylate and be selected from the halide ions of chloride ion, bromide ion or iodide ion.Nucleophilic reagent can be primary amine or the secondary amine in the presence of alkali.Alkali can be excessive amine nucleophilic reagent, perhaps can be added to the alkali additive in the reaction mixture.Possible alkali additive is a metal carbonate, alkaline carbonate especially, metal oxide and oxyhydroxide, and tertiary amine base.Appropriate organic solvent is for example acetonitrile, diox, N, dinethylformamide, N-N-methyl-2-2-pyrrolidone N-, tetrahydrofuran (THF), methyl-sulphoxide, tetramethylene sulfone and C1-4 alcohol.
In method (d), reaction is undertaken by handle formula (II) nucleophilic reagent with formula (VIII) electrophilic reagent in inert solvent.Suitable leavings group L 3Comprise halide ions, particularly chloride ion or bromide ion.This reaction is generally for example carried out in the presence of the sodium hydride at non-nucleophilic base.Appropriate organic solvent is for example N-N-methyl-2-2-pyrrolidone N-, tetrahydrofuran (THF), the pure and mild methyl-sulphoxide of C1-4.This reaction is generally carried out under the boiling temperature of 0 ℃-solvent.
In method (e), G preferably represents azido-(N 3).Required reduction can be by for example Sn (II) or triphenylphosphine are handled formula (IX) compound and realized with appropriate reductant.Preferably, reductive agent is a triphenylphosphine, and this reduction is for example carried out in the tetrahydrofuran (THF) at suitable inert solvent.
In aforesaid method, it will be obvious to those skilled in the art that may need maybe amine, hydroxyl or other possible reactive group must be protected.Suitable protecting group and add and remove the detailed description of the method for protecting group can be referring to standard textbook " Protecting Groups in Organic Synthesis ", 2nd Edition (1991), Greene and Wuts.In a preferred embodiment, amine groups as carbamate derivatives for example the tert.-butoxy carbamate be protected.Therefore, R wherein 1Be H formula (Ia) compound can by with the carbamate protecting group from R wherein 1Be that carbamate groups is for example removed on the formula of tert.-butoxy carbamate groups (Ia) compound, and make easily.Removing carbamate groups can carry out in diox easily with hydrogenchloride.
The present invention includes salt form, the particularly formula of acid salt form (Ia) compound.Suitable salt comprises the salt that forms with organic acid and mineral acid.Such acid salt generally is a pharmacologically acceptable salt, although non-pharmacologically acceptable salt can be used for preparation and purifying The compounds of this invention.Therefore, preferred salt comprises the salt that forms with following acid: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, citric acid, tartrate, lactic acid, pyruvic acid, acetate, succsinic acid, fumaric acid, toxilic acid, methylsulfonic acid and Phenylsulfonic acid.
The salt of formula (Ia) compound can by with free alkali or its salt, enantiomorph or racemic modification and one or how normal suitable acid-respons form.This reaction can by be insoluble at salt wherein solvent or medium in or in salt is dissolved in wherein solvent, carry out, such solvent has for example water, diox, ethanol, tetrahydrofuran (THF) or ether, perhaps in solvent mixture, carry out, but the solvent vacuum is removed or is removed by lyophilize.This reaction can also be a replacement(metathesis)reaction, perhaps can carry out on ion exchange resin.
Some formulas (III), (V), (VI), (VIII) and (IX) intermediate formed the present invention on the other hand.
Formula (III) compound can make like this: with formula (IX) compound R wherein 1And R 2Suc as formula defining in (Ia), with the reaction of Organometallic derivatives shown in the W-M, wherein W defines suc as formula (Ia) is middle, and M represents metal residue for example lithium or magnesium halogenide.
Formula (IX) compound can make like this: (a) formula (II) compound and formula (XI) compound reaction as defined above
Figure A0180548900302
Wherein W and G are as defined above; Perhaps (b) formula (IV) compound and reaction of formula (XII) compound as defined above Wherein V, W and G are as defined above.
Formula (II), (IV), (VII), (X), (XI) and (XII) compound be that known or available currently known methods makes.The embodiment illustrated of this paper some such methods.Other suitable method it will be apparent to those skilled in the art that.
Midbody compound can use with the form of self or with the form of protection.The detailed description of the protecting group and the method for removing thereof can be referring to the standard textbook " Protecting groups in Organic Synthesis " of Greene and Wuts, 2nd Edition (1991).
Can use standard technique that The compounds of this invention and intermediate thereof are separated from its reaction mixture, and can be further purified if necessary.
Formula (Ia) compound can exist with enantiomeric form.Therefore, all enantiomorphs, diastereomer, racemic modification and composition thereof all are included in the scope of the present invention.For example fractional crystallization or HPLC separate various optically active isomers from the racemic mixture of compound can to use routine techniques.
Midbody compound also can exist with enantiomeric form, and can be used as pure enantiomorph, diastereomer, racemic modification or mixture use.
Formula (Ia) compound and pharmacologically acceptable salt, enantiomorph and racemic modification all are useful, because they have pharmacologically active in animal.Particularly, formula (I) and (Ia) compound have activity as the enzyme nitric oxide synthase inhibitors.More particularly, they are inhibitor that the enzyme nitricoxide synthase is induced isoform, therefore estimate can be used for treatment, for example as anti-inflammatory agent.They also have the purposes as the inhibitor of enzyme NOS neurons isoform.
Formula (I) and (Ia) compound and pharmacologically acceptable salt, enantiomorph and racemic modification can be used for treating or prevent wherein that the synthetic or excessively synthetic of nitricoxide synthase is the disease or the illness of paathogenic factor.Particularly, these compounds can be used for treating the inflammatory conditions in the Mammals that comprises the people.
The illness that can specifically mention has: osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, urarthritis and other arhritis conditions, inflamed joints; Eczema, psoriasis, dermatitis or other inflammatory dermatosis disease are for example tanned severely; The inflammatory eye conditions comprises uveitis, glaucoma and conjunctivitis; The lung disorder that relates to inflammation is asthma, bronchitis, chronic obstruction tuberculosis, the disease of pigeon breeder, farmer lung, adult respiratory distress syndrome for example; Microbemia, endotoxemia (septic shock), aphthous ulcer, oulitis, pyrosis (pyresis), pain, meningitis and pancreatitis; Disorder of gastrointestinal tract, comprise inflammatory bowel, regional ileitis, atrophic gastritis, varioliform gastritis, ulcerative colitis, celiaca, local ileitis, peptide ulceration, irritable bowel syndrome, reflux oesophagitis, owing to infect the gastrointestinal injury due to the Helicobacter pylori infection for example, perhaps because with the gastrointestinal injury due to the nonsteroidal anti-inflammatory drug treatment; Illness with other and inflammation-related.
Owing to have the pharmacologically active as the enzyme nitric oxide synthase inhibitors, these compounds also can be used for treatment and alleviate acute pain or intractable inflammatory pain or neurodynia or central pain.
Our special concern inflammatory bowel, rheumatoid arthritis, osteoarthritis, chronic obstruction tuberculosis and pain.
Formula (I) and (Ia) compound and pharmacologically acceptable salt, enantiomorph and racemic modification also can be used for treating or prevent disease or illness except above-mentioned disease or illness.For example, these compounds can be used for treating atherosclerosis, cyst fibrosis, the ypotension relevant with septic and/or toxic shock, be used for the treatment of the immunity system dysfunction, alleviate immunosuppression in the organ transplantation treatment as adjutant, be used for the control of diabetes outbreak, be used for keeping the pancreas function of diabetes, be used for the treatment of the vascular complication relevant and be used for that for example TNF or interleukin carry out combination therapy with cytokine with diabetes.
Formula (I) and (Ia) compound also can be used for treating anoxic, for example treat the anoxic in asystolia and the apoplexy, neurodegenerative disease, comprise for example local asphyxia of disease, anoxic, hypoglycemia, epilepsy, and the neurodegeneration in the wound (for example spinal cord and head injury) and/or neural downright bad, hyperbaric oxygen is fainted from fear and is poisoned, dementia is presenile dementia for example, Alzheimer and the dementia relevant with AIDS, Sydenham's chorea, Parkinson's disease, the Te Leite Cotard, huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, korsakoff's disease, the low energy sick relevant, somnopathy with brainpan, schizophrenia, autism, seasonal affective psychosis, jet lag and septic shock.Expectation formula (I) and (Ia) compound also show activity aspect following: prevention and reversing drug habituation or tolerance, for example to opiate and diaza cover drug resistance, treatment migraine and other vascular headache, neurogenic inflammation, treatment gi tract motility obstacle, cancer and guiding childbirth.
Our special concern apoplexy, Alzheimer, Parkinson's disease, multiple sclerosis, schizophrenia, migraine, cancer and septic shock.
Prevention with shown effect in the past disease or illness or think that the people's that the danger of this disease of trouble or illness has increased treatment is relevant especially.There is the people of the danger of suffering from specified disease or illness to comprise the people of family history or the people who has determined to be easy to especially take place this disease or illness by genetic test or screening with this disease or illness.
For above-mentioned treatment indication, dosage becomes along with used compound, administering mode and required treatment certainly.Yet, generally speaking, when compound is used with 1mg-2000mg/ days dosage, can obtain satisfied result in solid dosage.
Formula (Ia) compound and pharmaceutically acceptable derivative thereof can use with the form of self, perhaps with the wherein form use of compound or derivative and pharmaceutically acceptable assistant agent, the suitable pharmaceutical composition of diluent or carrier blended.Administration can by but be not limited in intestines (comprising per os, hypogloeeis or rectum), nose, intravenously, part or other parenteral route approach carry out.The ordinary method of selecting and preparing suitable pharmaceutical preparation for example is described in " Pharmaceuticals-The Science ofDosage Form Designs ", M.E.Aulton, and Churchill Livingstone is in 1988.Pharmaceutical composition preferably comprises less than 80%, be more preferably less than 50% formula (Ia) compound or its pharmacologically acceptable salt, enantiomorph or racemic modification.
The present invention also provides the method for preparing such pharmaceutical composition, comprises each component is mixed.
For the purpose of favourable, formula (I) and (Ia) compound and pharmaceutically acceptable derivative thereof can also be united use with cox 2 inhibitor.Particularly preferred cox 2 inhibitor is Celecoxib and MK-966.Nos inhibitor and cox 2 inhibitor can be formulated in the same pharmaceutical composition that is used for using with single dose unit, perhaps each component are prepared individually, and the dosage of Fen Geing can simultaneously or be used successively like this.
Illustrate the present invention by the following example, but these embodiment are restrictive anything but.
Embodiment 12-(3-amino-1-phenyl propoxy-)-4-benzyl chloride nitrile hydrochloride is (3-hydroxyl-3-phenyl propyl) carboxylamine 1 a), 1-dimethyl ethyl ester
With α-(2-amino-ethyl) phenylcarbinol (1.21g 8mmol) is dissolved in the anhydrous tetrahydro furan (50ml), use successively tert-Butyl dicarbonate (1.92g, 8.8mmol) and triethylamine (1.34ml 9.6mmol) handles, and this mixture was stirred 18 hours.With this reaction mixture evaporation, resistates is eluted from the flash chromatography post, use ether/isohexane (1: 1) as eluent, obtained product (974mg, 48%), be the heavy-gravity yellow oil. 1H NMR 300MHz (CDCl 3) 7.35 (4H, m), 7.26 (1H, m), 4.89 (1H, br s), 4.75 (1H, m), 3.49 (1H, br m), 3.17 (2H, m), 1.86 (2H, m), 1.45 (9H, s) .b) 2-(3-amino-1-phenyl propoxy-)-4-benzyl chloride nitrile hydrochloride
(67mg 2.56mmol) is dissolved in the toluene (50ml) triphenylphosphine, and this solution is cooled to 0 ℃.Drip the diazonium dicarboxylate (45mg, 2.56mmol), and with this solution stirring 20 minutes.The 4-chloro-2-hydroxy benzonitrile of dropping in toluene (25ml) and tetrahydrofuran (THF) (10ml) (36mg 2.34mmol), is added in (3-hydroxyl-3-phenyl propyl) carboxylamine 1 in the toluene (25ml) then, and 1-dimethyl ethyl ester (59mg, 2.34mmol).With a weekend this reaction mixture being warmed to room temperature, evaporation, and resistates eluted from the flash chromatography post uses 10% ether/isohexane as eluent, has obtained the required product that protects as t-butyl carbamate.Product and 4M hydrogenchloride De dioxane solution (8ml) were stirred 2 hours,, and develop resistates, obtained this title compound (64mg, 8.5%), be colorless solid with anhydrous diethyl ether with solvent evaporation.MS?APCI+ve m/z?287([M+H) +). 1H?NMR?300MHz(d 6-DMSO)8.02(3H，br?s)，7.79(1H，d)，7.44-7.29(5H，m)，7.22(1H，d)，7.16(1H，d?of?d)，5.88(1H，m)，2.93(2H，br?m)，2.32(1H，m)，2.19(1H，m).
Embodiment 24-chloro-2-(3-(methylamino)-1-phenyl propoxy-) benzonitrile hydrochloride is 3-hydroxyl-3-phenyl propyl a)) methyl carbamic acid 1,1-dimethyl ethyl ester
[2-(methylamino) ethyl] phenylcarbinol that will be in methyl alcohol (150ml) (10.8g, 65.5mmol) use successively tert-Butyl dicarbonate (14.7g, 67.4mmol) and triethylamine (19.0ml 136mmol) handles, and this reaction mixture was stirred 4 hours.With solvent evaporation, and resistates eluted from the flash chromatography post, use ether/isohexane (1: 1), obtained required product (15.7g, 90%), be heavy-gravity oily matter as eluent.GC/MS m/ z 165 (M-100) +.b) 4-chloro-2-[3-(methylamino)-1-phenyl propoxy-] the benzonitrile hydrochloride
In nitrogen atmosphere, stir under, with triphenylphosphine anhydrous tetrahydro furan (10ml) in of 2 fens clockwise (0.38g, 1.46mmol) middle dropping diisopropyl azodiformate (0.29ml, 1.46mmol).This reaction mixture was stirred 20 minutes, be added in the 4-chloro-2-hydroxy benzonitrile (0.22g in the anhydrous tetrahydro furan (5ml) then, 1.46mmol), after 5 minutes, be added in the 3-hydroxyl-3-phenyl propyl in the anhydrous tetrahydro furan (5ml)) methyl carbamic acid 1, (0.39g 1.46mmol), and stirs this reaction mixture and spends the night 1-dimethyl ethyl ester.This mixture is diluted with ethyl acetate, use successively 10% aqueous sodium carbonate (2 * 50ml) and the salt water washing, use the magnesiumcarbonate drying.With solvent evaporation, resistates is eluted from the flash chromatography post, at first use ether/isohexane (1: 1) wash-out, use ether/isohexane (3: 7) more clarifying fraction of wash-out more then, obtained the product of acid amides protection.Itself and 4M hydrogenchloride De dioxane solution (5ml) were stirred 1 hour, and evaporation is developed resistates with ether, has obtained this title compound (96mg, 20%), is colorless solid.MS?APCI+ve? m/z?301([M+H] +). 1H?NMR?300MHz(d 6-DMSO)7.78(1H，d)，8.93(2H，br?s)，7.44-7.31(5H，m)，7.27(1H，d)，7.16(1H，d?of?d)，5.91(1H，m)，2.98(2H，m)，2.57(3H，s)，2.41-2.15(2H，m).
Embodiment 34-bromo-2-[(1R)-and 3-(methylamino)-1-phenyl propoxy-] a) [(3R)-3-hydroxyl-3-phenyl propyl] methyl carbamic acid 1 of benzonitrile hydrochloride, 1-dimethyl ethyl ester
Method preparation according to embodiment 2 (a) has obtained required product (6.0g, 78%), is heavy-gravity oily matter.MS APCI+ve m/ z 166 ([M-100+H] +) .b) [(3R)-and 3-(5-bromo-2-cyano-benzene oxygen)-3-phenyl propyl] methyl carbamic acid 1, the 1-dimethyl esters
Will [(3R)-and 3-hydroxyl-3-phenyl propyl] methyl carbamic acid 1, (0.4g, 1.5mmol) (0.3g 1.5mmol) is dissolved in the tetrahydrofuran (THF) (10ml) 1-dimethyl ethyl ester with 4-bromo-2-fluorine benzonitrile.(0.08g 2.0mmol), and stirs this mixture 4 hours to add 60% sodium hydride.This reaction mixture of water quenching is used ethyl acetate extraction then, uses dried over mgso, filters and rotary evaporation.By purified by flash chromatography, as eluent, obtained required product (0.49g, 73%) with 20% ethyl acetate/hexane, be colorless oil.MS APCI+ve m/ z 345/7 ([M-100+H] +) .c) 4-bromo-2-[(1R)-3-(methylamino)-1-phenyl propoxy-] the benzonitrile hydrochloride
Will [(3R)-and 3-(5-bromo-2-cyano-benzene oxygen)-3-phenyl propyl] methyl carbamic acid 1, (0.45g 1mmol) stirred 4 hours in 4M hydrogenchloride De dioxane solution (10ml) the 1-dimethyl esters.With solvent evaporation, handle resistates with ether, obtained required product (0.34g, 89%), be white solid.MS?APCI+ve? m/z?345/7([M+H] +). 1H?NMR?300MHz(d 6-DMSO)9.03(2H，s)，7.71(1H，d)，7.41-7.45(5H，m)7.36(1H，m)，7.27(1H，d)，5.94(1H，m)，2.94-3.04(2H，m)，2.56(3H，s)，2.31-2.40(1H，m)，2.19-2.26(1H，m).
Embodiment 4 γ-R-(2-bromo-5-chlorophenoxy)-Corvitin hydrochloride
With α-[2-(methylamino) ethyl]-(α 1R)-phenylcarbinol (0.395g 2.39mmol) is dissolved in the methyl-sulphoxide (3ml), and add 60% sodium hydride (0.19g, 4.78mmol).40 ℃ of heating 30 minutes, (0.5g 2.39mmol), and stirred this mixture 20 hours at 50 ℃ to add 1-bromo-4-chloro-2-fluorobenzene with this mixture.This mixture is cooled to room temperature, and the water quenching is handled, and uses ethyl acetate extraction, uses dried over mgso, filters and evaporation.By the purified by flash chromatography resistates, as eluent, obtained required product (0.47g, 50%) with the solution of 5%7M ammonia-methyl alcohol in methylene dichloride, be white solid.MS?APCI+ve? m/z?354/5/6/7/8([M+H] +). 1H?NMR?300MHz(d 6-DMSO)9.05(2H，s)，7.59(1H，d)，7.39-7.42(5H，m)，7.31-7.34(1H，m)，6.92(1H，d)，5.82(1H，m)，2.95-3.00(2H，m)，2.56(3H，s)，2.28-2.37(1H，m)，2.19-2.25(1H，m).
Embodiment 54-chloro-2-{[(1R)-and 3-chloro-1-phenyl propyl] the oxygen base) a) 4-chloro-2-{[(1R of benzonitrile hydrochloride)-3-chloro-1-phenyl propyl] the oxygen base } benzonitrile
Under nitrogen atmosphere, in ice bath, with (S)-α-(2-chloroethyl) phenylcarbinol (170mg, 1.0mmol), 4-chloro-2-hydroxy benzonitrile (154mg, 1.0mmol.) and triphenylphosphine (260mg, 1.0mmol.) in anhydrous tetrahydro furan (5ml), stir, add simultaneously diethyl azodiformate (0.16ml, 1.0mmol.).This reaction mixture is warmed to room temperature, and stirred 3 days.With solvent evaporation, and resistates is dissolved in the toluene, is added to the top of flash chromatography post,, obtained product (220mg, 72%), be heavy-gravity oily matter with 10% ether/isohexane wash-out. 1H NMR 300MHz (CDCl 3) 7.21 (1H, d), 7.24-7.33 (5H, m), 6.92 (1H, d of d), 6.75 (1H, d), 5.43 (1H, m), 3.80 (1H, m), 3.56 (1H, m), 2.50 (1H, m), 2.18 (1H, m) .b) 4-chloro-2-{[(1R)-3-iodo-1-phenyl propyl] the oxygen base } benzonitrile
With 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base } benzonitrile (220mg 0.718mmol) is dissolved in the acetone (20ml) of using sodium iodide saturated in advance, and with this vlil 18 hours.With this reaction mixture cooling, filter, evaporate, and resistates is distributed between water and ethyl acetate.Isolate organic layer, wash with water 2 times, and dry (using sal epsom).With solvent evaporation, obtained 0.24g (84%) product, be yellow oil.This product is directly used in next step without purifying.C) 4-chloro-2-{[(1R)-and 3-(methylamino)-1-phenyl propyl] the oxygen base } the benzonitrile hydrochloride
With 4-chloro-2-{[(1R)-3-iodo-1-phenyl propyl] the oxygen base } benzonitrile (240mg 0.604mmol.) is dissolved in the tetrahydrofuran (THF) (10ml), handles with 40% aqueous methylamine solution (5ml), and stirring at room 5 hours.Solvent removed in vacuo is dissolved in resistates in the water, and is extracted in the ethyl acetate, is dried (using sal epsom).With solvent evaporation, resistates and 4M hydrogenchloride De dioxane solution (5ml) were stirred 1 hour.With solvent evaporation, with resistates and ether azeotropic 2 times, with the ether development, obtained required product (155mg, 76%) at last, be khaki solid.MS?APCI+ve? m/z?301([M+H] +). 1H?NMR?300MHz(d 6-DMSO)8.86(2H，br?s)，7.79(1H，d)，7.44-7.31(5H，m)，7.26(1H，d)，7.16(1H，d?of?d)，5.90(1H，m)，3.01(2H，brm)，2.57(3H，t)，2.41-2.15(2H，m).
Embodiment 64-methoxyl group-2-[3-(methylamino)-1-phenyl amino-1-phenyl propoxy-] the benzonitrile hydrochloride
This title compound is the method by embodiment 2 (b), uses 2-hydroxyl-4-methoxyl group-benzonitrile to make, and has obtained 0.13g (27%) product, is vitreous solid.MS?APCI+ve? m/z?297([M+H] +). 1H?NMR?300MHz(d 6-DMSO)8.92(2H，br?s)，7.64(1H，d)，7.46-7.30(5H，m)，6.66(1H，d)，6.63(1H，d?of?d)，5.85(1H，m)，3.73(3H，s)，3.00(2H，br?m)，2.57(3H，s)，2.37-2.18(2H，m).
Embodiment 74-methyl-2-{[(1R)-3-(methylamino)-1-phenyl propyl] the oxygen base } the benzonitrile hydrochloride
This title compound is the method by embodiment 1 (b), the initial use [(3R)-and 3-hydroxyl-3-phenyl propyl] methyl carbamic acid 1,1-dimethyl ethyl ester and 2-hydroxy-4-methyl benzonitrile make, and have obtained 0.35g (73%) product, are colorless solid.MS?APCI+ve? m/z?281([M+H] +). 1H?NMR?300MHz(d 6-DMSO)9.09(2H，br)，7.58(1H，d)，7.39-7.46(4H，m)，7.32(1H，m)，7.02(1H，s)，6.87(1H，d)，5.84(1H，m)，3.00(2H，m)，2.55(3H，s)，2.30-2.39(1H，m)，2.19-2.25(1H，m)，2.25(3H，s).
Embodiment 8R-γ-(2, the 5-dichlorophenoxy)-N-methyl-2-thiophene propylamine is 2-[(1R a))-3-chloro-1-(2, the 5-dichlorophenoxy) propyl group] thiophene
At 0 ℃, diethyl azodiformate (0.7ml) is added to S-α-(2-chloroethyl)-2-thiophen(e)alcohol (657mg), 2, in 5-chlorophenesic acid (607mg) and the solution of triphenylphosphine (1.17g) in toluene (10ml), and this mixture stirred 3 hours at 0 ℃, stirred 14 hours at 20 ℃.Solvent removed in vacuo by silica gel chromatography purifying resistates, with gasoline-ether (9: 1) wash-out, has obtained this title compound, is colorless oil (788mg). 1H NMR (CDCl 3) 7.32-6.84 (6H, m), 5.72-5.65 (1H, m), 3.87-3.81 (1H, m), 3.68-3.60 (1H, m), 2.69-2.58 (1H, m), 2.41-2.32 (2H, m) .b) 2-[(1R)-1-(2, the 5-dichlorophenoxy)-3-iodine propyl group] thiophene
Vlil in acetone (30ml) is 18 hours with step (a) product (788mg) and sodium iodide (4.5g).Solvent removed in vacuo adds entry, with ether with this mixture extraction 2 times.With organic layer drying (using sal epsom), evaporation, and,, obtained this title compound with gasoline-ether (19: 1) wash-out by the silica gel chromatography purifying, be light yellow oil (742mg). 1H NMR (CDCl 3) 7.30-7.23 (2H, m), 7.09 (1H, d), and 6.99-6.86 (3H, m), 5.59-5.53 (1H, m), 3.47-3.39 (1H, m), and 3.29-3.21 (1H, m), 2.72-2.60 (1H, m), 2.47-2.36 (1H, m) R-γ-(2, the 5-dichlorophenoxy)-N-methyl-2-thiophene propylamine fumarate .c)
With the solution stirring of step (b) product (217mg) in 40% aqueous methylamine solution (5ml) and tetrahydrofuran (THF) (5ml) 2.5 days.Solvent removed in vacuo adds entry, with ethyl acetate with this mixture extraction 3 times.With organic layer drying (using sodium sulfate), evaporation, and by the silica gel chromatography purifying, methanol solution (19: the 1) wash-out with methylene dichloride-7M ammonia has obtained oily matter (116mg).The methanol solution that in the solution of this oily matter in ethyl acetate, adds fumaric acid (43mg).Collecting precipitation, drying has obtained this title compound, is tiny white solid (127mg).MS(APCI) m/z316[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.53(1H，d)，7.44(1H，d)，7.30(1H，s)，7.21(1H，d)，7.04-6.95(2H，m)，6.43(2H，s)，6.05(1H，dd)，2.97-2.85(2H，m)，2.49(3H，s)，2.44-2.16(2H，m).
Embodiment 9S-γ-(2, the 5-dichlorophenoxy)-N-methyl-2-thiophene propylamine is 2-[(1S a))-3-chloro-1-(2, the 5-dichlorophenoxy) propyl group] thiophene
This title compound is the method according to embodiment 8 (a), uses R-α-(2-chloroethyl)-2-thiophen(e)alcohol to make. 1H NMR 300MHz (CDCl 3) 7.32-6.84 (6H, m), 5.72-5.65 (1H, m), 3.87-3.81 (1H, m), 3.68-3.60 (1H, m), 2.69-2.58 (1H, m), 2.41-2.32 (1H, m) .b) 2-[(1S)-1-(2, the 5-dichlorophenoxy)-3-iodine propyl group 1 thiophene
This title compound is the method according to embodiment 8 (b), uses step (a) product to make. 1H NMR 300MHz (CDCl 3) 7.30-7.23 (2H, m), 7.09 (1H, d), and 6.99-6.86 (3H, m), 5.59-5.53 (1H, m), 3.47-3.39 (1H, m), and 3.29-3.21 (1H, m), 2.72-2.60 (1H, m), 2.47-2.36 (1H, m) S-γ-(2, the 5-dichlorophenoxy)-N-methyl-2-thiophene propylamine fumarate .c)
This title compound is the method according to embodiment 8 (c), uses step (b) product to make.MS(APCI) m/z?316[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.53(1H，d)，7.44(1H，d)，7.30(1H，s)，7.21(1H，d)，7.04-6.95(2H，m)，6.43(2H，s)，6.04-6.60(1H，m)，2.95-2.84(2H，m)，2.48(3H，s)，2.43-2.29(1H，m)，2.23-2.13(1H，m).
Embodiment 102-[[(3R)-and 3-(2, the 5-dichlorophenoxy)-3-(2-thienyl) propyl group] amino] the ethanol fumarate
Solution stirring in tetrahydrofuran (THF) (5ml) is 2.5 days with embodiment 8 (b) product (214mg) and thanomin (0.1ml).Solvent removed in vacuo adds entry, with ethyl acetate with this mixture extraction 3 times.With organic layer drying (using sodium sulfate), evaporation, and by the silica gel chromatography purifying, methanol solution (19: the 1) wash-out with methylene dichloride-7M ammonia has obtained oily matter (116mg).In the solution of this material in ethyl acetate, add the solution of fumaric acid (43mg) in methyl alcohol.Collecting precipitation, and dry, obtained this title compound, be tiny colorless solid (127mg).MS(APCI) m/z?346[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.51(1H，d)，7.43(1H，d)，7.32(1H，s)，7.20(1H，d)，7.01-6.98(2H，m)，6.43(2H，s)，6.01(1H，t)，3.53(2H，t)，2.84-2.74(4H，m)，2.38-2.28(1H，m)，2.18-2.1(1H，m).
Embodiment 114-chloro-2-{[(1R)-and 3-(4-methyl isophthalic acid-piperazinyl)-1-phenyl propyl] the oxygen base }-the benzonitrile dihydrochloride
With 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base-benzonitrile (0.17g), 4-methylpiperazine (0.2g), potassiumiodide (0.02g) in N-Methyl pyrrolidone (5ml) in 100 ℃ of heating 3 hours.This reaction mixture is cooled to room temperature, pours in the water, and product is extracted in the ethyl acetate.With this ethyl acetate solution water, salt water washing, use dried over mgso, and be evaporated to driedly, obtained oily matter.Develop this oily matter with the diethyl ether solution of 1M hydrogenchloride, obtained product (0.135g) as dihydrochloride.MS?APCI+ve? m/z?370[(M+H) +]. 1H?NMR(d 6-DMSO)7.78(1H，dd)，7.33-7.48(5H，m)，7.29(1H，s)，7.16(1H，dd)，5.89(1H，m)，3.2-4.8(10H，m)，2.82(3H，s)，2.45-2.50(2H，m).
Embodiment 124-chloro-2-{[(1R)-and 3-(4-hydroxyl-piperidino)-1-phenyl propyl] the oxygen base }-the benzonitrile fumarate
With 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base }-benzonitrile and 4-hydroxy-piperdine react as described in example 11 above, obtained this title compound.By converting it into fumarate with 1 normal fumaric acid methanol solution development.MS?APCI+ve? m/z?371[(M+H) +]. 1H?NMR(d 6-DMSO)7.51(1H，d)，7.26-7.38(5H，m)，6.97(1H，d)，6.9(1H，s)，6.70(2H，s)，5.50(1H，m)，3.65-3.75(1H，m)，2.85-2.95(2H，m)，2.6-2.82(2H，m)，2.35-2.50(2H，m)，2.2-2.3(1H，m)，2.05-2.01(1H，m)，1.86-2.0(2H，m)，1.6-1.7(2H，m).
Embodiment 134-chloro-2-{[(1R)-and the 3-[(2-hydroxyethyl) methylamino]-the 1-phenyl propyl] the oxygen base }-the benzonitrile hydrochloride
With 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base }-benzonitrile and (2-methylamino) ethanol reacts as described in example 11 above, obtained this title compound.MS?APCI+ve? m/z?345[(M+H) +]. 1H?NMR(CDCl 3)7.48(1H，d)，7.31-7.45(5H，m)，7.00(1H，dd)，6.88(1H，d)，5.66(1H，dd)，5.01(1H，bs)，4.00(2H，m)，3.27(1H，bs)，2.92(3H，s)，2.53-2.60(6H，m).
Embodiment 144-chloro-2-{[(1R)-and 3-(4-morpholinyl)-1-phenyl propyl] the oxygen base }-the benzonitrile fumarate
With 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base }-benzonitrile and morpholine react as described in example 11 above, obtained this title compound.By converting it into fumarate with 1 normal fumaric acid methanol solution development.MS?APCI+ve? m/z?357[(M+H) +]. 1H?NMR(d 6-DMSO)7.49(1H，dd)，7.29-7.38(5H，m)，7.29(1H，dd)，6.92(1H，d)，6.76(2H，s)，5.42(1H，m)，3.71(4H，m)，2.5-2.7(2H，m)，2.43-2.49(4H，m)，2.24-2.31(1H，m)，2.02-2.22(1H，m).
Embodiment 154-chloro-2-{[(1R)-3-[(3R)-3-hydroxyl pyrrolidine base]-the 1-phenyl propyl] the oxygen base }-the benzonitrile fumarate
With 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base-benzonitrile with (3R)-the 3-hydroxyl pyrrolidine reacts as described in example 11 above, obtained this title compound.By converting it into fumarate with 1 normal fumaric acid methanol solution development.MS?APCI+ve? m/z?357/359[(M+H) +]. 1H?NMR(d 6-DMSO)7.76(1H，d)，7.25-7.45(5H，m)，7.20(1H，s)，7.10(1H，dd)，6.55(2H，s)5.75(1H，m)，4.24(1H，m)，2.95(1H，m)，2.91(1H，m)，2.82(2H，m)，2.51(2H，m)2.18-2.3(1H，m)，1.97-2.05(2H，m)，1.62-1.64(1H，m).
Embodiment 164-chloro-2-{[(1R)-3-[(3S)-3-hydroxyl pyrrolidine base]-the 1-phenyl propyl] the oxygen base }-the benzonitrile fumarate
With 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base-benzonitrile with (3S)-the 3-hydroxyl pyrrolidine reacts as described in example 11 above, obtained this title compound.By converting it into fumarate with 1 normal fumaric acid methanol solution development.MS?APCI+ve? m/z?357/359[(M+H) +]. 1H?NMR(d 6-DMSO)7.76(1H，d)，7.25-7.45(5H，m)，7.20(1H，s)，7.10(1H，dd)，6.55(2H，s)5.75(1H，m)，4.24(1H，m)，2.95(1H，m)，2.91(1H，m)，2.82(2H，m)，2.51(2H，m)，2.18-2.3(1H，m)，1.97-2.05(2H，m)，1.62-1.64(1H，m).
Embodiment 172-{[(1R)-and 3-amino-1-phenyl propyl] the oxygen base }-a) 5-fluoro-2-hydroxy-4-methyl benzonitrile of 5-fluoro-4-methyl benzonitrile fumarate
0 ℃, stir under, (48ml adds 4-fluoro-3-methylphenol (4.44ml, 40mmol) solution in methylene dichloride (40ml), methylthiocyanide methylthiocyanate (3.3ml in 48mmol) successively to the solution of 1M boron trichloride in methylene dichloride, 48mmol) and Aluminum chloride anhydrous (5.4g, 40mmol).With this reaction mixture reflux 3 hours, and in stirred overnight at room temperature.With solvent evaporation, replace with ethylene dichloride, and be added in ice and the 4N sodium hydroxide (132ml).With this mixture reflux 0.5 hour under agitation, be cooled to room temperature, isolate organic layer, wash water layer with ethylene dichloride.With 2M hydrochloric acid with the water layer acidifying, by filtering the solid that collecting precipitation goes out, and the water thorough washing.In being dissolved in solid in the ethyl acetate, use dried over mgso, evaporation, and under ice-cooled, develop resistates with isohexane, and obtained 3.5g (58%) book title compound, be colorless solid. 1H NMR 300MHz (d 6-DMSO) 7.12 (1H, d), 6.81 (1H, d), 2.29 (3H, s) .b) 2-[[(1R)-3-chloro-1-phenyl propyl] the oxygen base]-5-fluoro-4-methyl benzonitrile
This suitable compound is the method by embodiment 5 (a), uses 5-fluoro-2-hydroxy-4-methyl benzonitrile and S-α-(2-chloroethyl) phenylcarbinol to make. 1H NMR 300MHz (CDCl 3) 7.41-7.29 (5H, m), 7.16 (1H, d), 6.63 (1H, d), 5.45 (1H, m), 3.89 (1H, m), 3.63 (1H, m), 2.55 (1H, m), 2.24 (1H, m), 2.17 (3H, s) .c) 5-fluoro-2-[[(1R)-3-iodo-1-phenyl propyl] the oxygen base]-4-methyl benzonitrile
This suitable compound is the method by embodiment 5 (b), uses 5-fluoro-2-[[(1R)-3-chloro-1-phenyl propyl] the oxygen base]-5-fluoro-4-methyl benzonitrile makes. 1H NMR 300MHz (CDCl 3) 7.39-7.31 (5H, m), 7.16 (1H, d), 6.64 (1H, d), 5.33 (1H, m), 3.47 (1H, m), 3.28 (1H, m), 2.54 (1H, m), 2.31 (1H, m), 2.18 (3H, s) .d) 2-[[(1R)-3-azido--1-phenyl propyl] the oxygen base]-5-fluoro-4-methyl benzonitrile
With iodine compound 17 (c) (504mg, 1.28mmol) and sodiumazide (124mg 1.91mmol) stirred in methyl-sulphoxide (5ml) and water (2) 3 hours.This reaction mixture is poured in the water, used ethyl acetate extraction, use the salt water washing then, and use anhydrous magnesium sulfate drying.With solvent evaporation, obtained 361mg (91%) light yellow oil. 1H NMR 300MHz (CDCl 3) 7.39-7.29 (5H, m), 7.16 (1H, d), 6.59 (1H, d), 530 (1H, m), 3.67 (1H, m), 3.46 (1H, m), 2.31 (1H, m), 2.17 (3H, t), 2.08 (1H, m) .e) 2-([(1R)-and 3-amino-1-phenyl propyl] the oxygen base }-5-fluoro-4-methyl benzonitrile fumarate
Will the trinitride 17 (d) in the tetrahydrofuran (THF) (15ml) use successively triphenylphosphine (512mg, 1.95mmol) and water (1.5ml) handle.This reaction mixture is poured in the water, and reflux 2 hours under agitation, evaporation, resistates is eluted from the flash chromatography post, earlier use eluent ethyl acetate, use the methanol solution/methylene dichloride wash-out of 5%7M ammonia then, obtained 186mg heavy-gravity oily matter.It is dissolved in the minimum ethanol, and (75.7mg 0.652mmol) handles, and is warmed to dissolving fully, and handles until becoming muddy with ether with fumaric acid.After leaving standstill 1 hour, collect crystal,, and, obtained this title compound of 159mg (30%), be colorless solid 40 ℃ of vacuum-dryings with the minor amounts of acetonitrile washing by filtering.MS?APCI+ve? m/z?285[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.63(1H，d)，7.43-7.28(5H，m)，7.08(1H，d)，6.39(2H，s)，5.73(1H，m)，2.87(2H，t)，2.30-2.03(2H，m)，2.17(3H，s).
Embodiment 184-chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidyl) propoxy-] a) [3-hydroxyl-3-(2-pyrimidyl) propyl group] methyl carbamic acid 1 of benzonitrile hydrochloride, 1-dimethyl ethyl ester
Under nitrogen atmosphere, be cooled to being dissolved in 2-(tributyl stannyl) pyrimidine in-78 ℃ the anhydrous tetrahydro furan (10ml) (690mg, add in 1.87mmol) the 2.4M n-Butyl Lithium hexane solution (0.8ml, 1.87mmol).Stir after 0.5 hour, at-78 ℃ of methyl (3-oxopropyl) carboxylamine 1,1 dimethyl ethyl esters that are added in rapidly in the anhydrous tetrahydro furan (10ml).This reaction mixture is warmed to room temperature, handles with saturated aqueous ammonium chloride, and use ethyl acetate extraction, use the salt water washing, and use anhydrous magnesium sulfate drying.With solvent evaporation, resistates is eluted from the flash chromatography post, use 10% ethyl acetate/dichloromethane wash-out earlier, use 10% ethanol/methylene wash-out then, obtained 260mg (43%) book title compound, be the heavy-gravity yellow oil.MS APCI+ve m/ z 268[(M+H) +] .b) [3-(5-chloro-2-cyano group-4-fluorophenoxy)-3-(2-pyrimidyl) propyl group] methyl carbamic acid, 1,1-dimethyl ethyl ester
Will be at anhydrous N, (255mg, 0.955mmol) (60% mineral oil suspension, 40mg 0.955mmol) handle the alcohol 18 (a) in the dinethylformamide (15ml), and this reaction mixture stirred under nitrogen stop until effervesce with sodium hydride.Add 4-chloro-2,5-difluoro benzonitrile (166mg, 0.955mmol), and with this reaction mixture under nitrogen atmosphere in 40 ℃ of heating 1 hour.Should react cooling, and distribute between salt solution and ethyl acetate, and isolate organic layer, anhydrous magnesium sulfate drying is used in water (5 *) and salt water washing successively.With solvent evaporation, resistates is eluted from the flash chromatography post, use 30% ethyl acetate/isohexane as eluent, obtained 140mg (35%) book title compound, be heavy-gravity oily matter. 1H NMR 300MHz (CDCl 3) 8.76 (2H, d), 7.33 (1H, d), 7.26 (1H, m), 6.92 (1H, br m), (5.33 1H, br m), 3.65 (1H, br m), 3.41 (1H, m), 2.89 (3H, s), 2.45-2.30 (2H, m), 1.38 (9H, s) .c) 4-chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidyl) propoxy-] the benzonitrile hydrochloride
(140mg 0.333mmol) handles with 4M HCl De dioxane solution (10ml), and stirred 1 hour with carbamate 18 (b).By filtering the solid that collecting precipitation goes out, with the ether washing, and dry, obtained the required product of 97mg (80%), be colorless solid.MS?APCI+ve? m/z?321[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.98(2H，br?m)，8.88(2H，d)，8.04(1H，d)，7.52(1H，t)，7.41(1H，d)，5.90(1H，t)，3.12(2H，m)，2.58(2H，t)，2.49(3H，s).
Embodiment 194-chloro-5-fluoro-2-({ (1R)-1-(3-furyl)-3-[(2-methoxy ethyl) amino] propyl group } the oxygen base) a) (R)-α-(2-chloroethyl)-3-furfuralcohol of benzonitrile oxalate
This compound is that the preparation method according to embodiment 74 (d) divides two steps to be made by 1-(3-furyl)-2-propylene-1-ketone, has obtained colorless solid. 1H NMR 300MHz (CDCl 3) 7.43-7.41 (2H, m), 6.42 (1H, s), 4.98-4.92 (1H, m), 3.79-3,73 (2H, m), amino 2.30-2.10 (2H, m) .b) 4-chloro-5-fluoro-2-[{ (1R)-1-(3-furyl)-3-[(2-methoxy ethyl)] propyl group } the oxygen base) the benzonitrile oxalate
(100mg 0.62mmol) is dissolved in the tetrahydrofuran (THF) (5ml) with (R)-α-(2-chloroethyl)-3-furfuralcohol in room temperature.In this solution, add the suspension of 60% sodium hydride in mineral oil (37mg 0.93mmol), stirs this mixture 10 minutes, disposable then adding solid 4-chloro-2,5-difluoro benzonitrile (107.6mg, 0.62mmol).The gained mixture was stirred 1 hour, add entry (2ml) then, and with this mixture vacuum concentration.Resistates is distributed between methylene dichloride and water.Collect organic phase, use dried over mgso, filtration and vacuum concentration are to doing.The gained resistates is dissolved in N, in the dinethylformamide (2ml), and with sodium iodide (93mg, 0.62mmol), triethylamine (172 μ l, 1.24mmol) and the 2-methoxyethyl amine (107 μ l 1.24mmol) handle, then 60 ℃ of heating 72 hours.With this mixture cooling, filter, and, obtained this title compound of free alkali form via the reversed-phase HPLC purifying, it is handled with the saturated solution of 50% oxalic acid in ether.Collect the gained white solid via filtering, obtained this title compound (61mg, 28%).MS?APCI+ve? m/z3?53/355[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.02(1H，d)，7.82(1H，s)，7.70(1H，s)，7.59(1H，s)，5.72(2H，t)，3.57(2H，m)，3.31(3H，s)，3.16(2H，m)，3.09-2.98(2H，b)，2.37(1H，bm)，2.27(1H?br?m).
Embodiment 204-methoxyl group-2-[[(1R)-3-(methylamino)-1-phenyl propyl] the oxygen base]-benzonitrile hydrochloride (a) [(3R)-and 3-(2-cyano group-5-methoxyl group phenoxy group)-3-phenyl propyl] methyl carbamic acid 1,1-dimethyl ethyl ester
Under nitrogen atmosphere, to 2-cyano group-5-methoxyphenol (149mg, 1.00mmol) and [(3S)-and 3-hydroxyl-3-phenyl propyl] methyl carbamic acid 1,1-dimethyl ethyl ester (265mg, 1.00mmol) add triphenylphosphine (290mg in the mixture that is stirring in tetrahydrofuran (THF) (10ml), 1.10mmol), add then the diazonium dicarboxylate (192mg, 1.10mmol).Stirring at room 24 hours, be evaporated to dried then this reaction mixture.Resistates is eluted from the flash chromatography post, use 30% ethyl acetate/isohexane, obtained 275mg (69%) book title compound, be oily matter as eluent. 1H NMR 300MHz (CDCl 3) 7.26-7.45 (6H, m), 6.43 (1H, dd), 6.25 (1H, s), 5.19 (1H, bs), 3.67 (3H, s), 3.50 (2H, bs), 2.87 (3H, s), 2.25 (1H, bs), 2.10 (1H, m), 1.38 (9H, s) .b) 4-methoxyl group-2-[[(1R)-3-(methylamino)-1-phenyl propyl] the oxygen base]-the benzonitrile fumarate
Will [(3R)-and 3-(2-cyano group-5-methoxyl group phenoxy group)-3-phenyl propyl] (270mg 0.682mmol) is dissolved in the dioxane solution (8ml) of 4M hydrogenchloride methyl carbamic acid 1,1 dimethyl ethyl ester.With gained solution stirring at room 20 hours, then with the sodium hydrogen carbonate solution dilution that contains ammonia, and with dichloromethane extraction 3 times.With the organic phase salt water washing that merges, use dried over mgso then.With solvent evaporation, resistates is dissolved in the ethanol.The ethanolic soln that in this solution, adds fumaric acid, and with solvent evaporation.With resistates recrystallization from ethanol/ether, obtained this title compound of 128mg (46%), be white solid.MS?APCI+ve? m/z?297[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.62(1H，d)，7.29-7.44(5H，m)，6.61(2H，m)，6.44(2H，s)，5.74(1H，dd)，3.71(3H，s)，2.89(2H，t)，2.50(3H，s)，2.22(1H，m)，2.11(1H，m).
Embodiment 21 γ-(2-bromo-5-fluorophenoxy)-N-methyl-amphetamine fumarate
This compound is the method by embodiment 2 (b), use (3-hydroxyl-3 phenyl propyl) methyl carbamic acid 1,1-dimethyl ethyl ester and 2-bromo-5-fluorophenol make, and change into this title compound (white solid) (11.3mg, 3.2%) of fumarate form.MS?APCI+ve? m/z?338[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.61-7.56(1H，dd)，7.40-7.30(5H，m)，6.90-6.86(1H，dd)，6.75-6.69(1H，dt)，6.43(2H，s)，5.69-5.65(1H，m)，3.35(3H，s)，2.90-2.845(2H，t)，2.27-2.06(2H，m).
Embodiment 22 (R)-γ-(5-bromo-2-chlorophenoxy)-Corvitin fumarate
According to being similar to the method for describing among the embodiment 2 (b), will [(3S)-and 3-hydroxyl-3-phenyl propyl] methyl carbamic acid 1,1-dimethyl ethyl ester and 5-bromo-2-chlorophenol react, and have obtained this title compound (white solid) (449mg, 52%) of fumarate form. 1H?NMR?400MHz(d 6-DMSO)7.40-7.36(5H，m)，7.34-7.29(1H，m)，7.19-7.19(1H，d)，7.10-7.08(1H，dd)，6.44(2H，s)，5.72-5.70(1H，m)，2.90-2.86(2H，t)，2.52-2.48(3H，s).2.29-2.05(2H，m).
Embodiment 23 (R)-γ-(2-bromo-5-nitro-phenoxy)-Corvitin fumarate
According to being similar to the method for describing among the embodiment 2 (b), will [(3S)-and 3-hydroxyl-3-phenyl propyl] methyl carbamic acid 1,1-dimethyl ethyl ester and 2-bromo-5-nitrophenols react, and have obtained this title compound (yellow solid) (278mg, 49.8%) of fumarate form.MS?APCI+ve? m/z?365[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.91-7.88(1h，d)，7.72-7.67(2H，m)，7.46-7.28(5H，m)，6.43(2H，s)，5.88-5.84(1H，dd)，2.93-2.89(2H，t)，2.53-2.43(3H，s)，2.38-2.10(2H，m).
Embodiment 244-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-methoxy ethyl) amino]-the 1-phenyl propyl] the oxygen base]-the benzonitrile oxalate
With 4-chloro-5-fluoro-2-[[(1R)-3-iodo-1-phenyl propyl] the oxygen base]-benzonitrile (0.481mmol, the method by embodiment 43 (b) makes) is dissolved in the 2-methoxy ethyl amine (2.4mmol), and with the gained yellow solution stirring at room 24 hours.Excess amine is evaporated, and resistates is distributed between sodium bicarbonate aqueous solution and ethyl acetate.Crude product is extracted in the ethyl acetate, uses anhydrous sodium sulfate drying then.Filter, evaporation has obtained oily matter, by chromatography and reversed-phase HPLC purifying.Use oxalic acid and methyl alcohol that resistates is changed into oxalate, obtained this title compound of 48mg (22%).MS?APCI+ve? m/z?363[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.03-8.01(1H，d)，7.45-7.41(5H，m)，7.37-7.32(1H，m)，5.79-5.76(1H，m)，3.55-3.52(2H，t)，3.29(3H，s)，3.11-2.97(2H，m)，2.52-2.49(2H，m)，2.34-2.17(2H，m).
Embodiment 254-chloro-2-{[(1R)-and 3-(cyclopropyl amino)-1-phenyl propyl] the oxygen base }-5-fluorine benzonitrile oxalate
(341mg 2mmol) is dissolved in the tetrahydrofuran (THF) (10ml), and with the suspension (480mg of 60% sodium hydride in mineral oil with (R)-α-(2-chloroethyl) phenylcarbinol, 3mmol) handle, after 10 minutes, add 4-chloro-2,5-difluoro benzonitrile (347mg, 2mmol).Stirring at room 18 hours, use methyl alcohol (1ml) and water (10ml) to handle then successively in this mixture.By being heated and apply nitrogen gas stream at 80 ℃, reactor removes tetrahydrofuran (THF).In case, be about to residue extracted in methylene dichloride with the tetrahydrofuran (THF) evaporation, use dried over mgso, and vacuum concentration.The gained material is dissolved in the dimethyl formamide (8ml) again, with sodium iodide (305mg, 2.03mmol), triethylamine (565 μ l, 4.06mmol) and cyclopropylamine (114mg 2mmol) handles, and heats 5 days at 60 ℃.This mixture is filtered, with thick reaction product via the RPHPLC purifying.Then the compound of purifying is handled with the saturated solution of 50% oxalic acid in ether, obtained 74mg via filtering the white powder of collecting.MS?APCI+ve? m/z?345/347[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.97-7.87(m，1H)，7.53-7.25(m，6H)，5.69(m，1H)，3.28-3.07(m，2H)，2.80-2.68(m，1H)，2.45-2.29(m，1H)，2.29-2.12(m，1H)，0.85-0.74(m，4H).
Embodiment 264-chloro-2-{[(1R)-and 3-(cyclopropyl amino)-1-(3-furyl) propyl group] the oxygen base }-5-fluorine benzonitrile oxalate
This compound makes like this: by the method for embodiment 25, at first use (R)-α-(2-chloroethyl)-3-furfuralcohol (321mg, 2mmol) with 4-chloro-2,5-difluoro benzonitrile (347mg, 2mmol), change into iodine compound via in-situ transesterification then and handle with cyclopropylamine and to transform the cost title compound.Handle this free alkali with the saturated solution of 50% oxalic acid in ether.Collect the gained white solid via filtering, obtained this title compound (14mg, 1.6%).MS?APCI+ve? m/z?335/337[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.01(d，1H)，7.70(s，1H)，7.70(s，1H)，7.59(d，1H)，6.53(s，1H)，5.72(t，1H)，3.15-2.99(m，2H)，2.97-2.87(m，1H)，2.40-2.26(m，1H)，2.24-2.09(m，1H)，0.78-0.66(m，4H).
Embodiment 274-chloro-2-{ (1R)-3-(cyclopropyl amino)-1-(3-thienyl) propyl group] the oxygen base }-5-fluorine benzonitrile oxalate
This compound makes like this: by the method for embodiment 25, at first use (R)-α-(2-chloroethyl)-3-thiophen(e)alcohol (embodiment 74 (d)) and 4-chloro-2,5-difluoro benzonitrile changes into iodine compound via in-situ transesterification then and handles with cyclopropylamine and transforms the cost title compound.Handle this free alkali with the saturated solution of 50% oxalic acid in ether.Collect the gained white solid via filtering, obtained this title compound (24mg, 3%).MS?APCI+ve? m/z?351[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.02(d，1H)，7.60(s，2H)，7.50(d，1H)，7.14(d，1H)，5.83(t，1H)，3.14-2.99(m，2H)，2.76-2.62(m，1H)，2.42-2.29(m，2H)，2.27-2.13(m，2H)，0.84-0.63(m，4H).
Embodiment 284-bromo-2-{[(1R)-and 3-(cyclopropyl amino)-1-(phenyl) propyl group] the oxygen base }-5-fluorine benzonitrile oxalate
This compound makes like this: by the method for embodiment 25, at first use (R)-α-(2-chloroethyl) phenylcarbinol and 4-bromo-2,5-difluoro benzonitrile changes into iodine compound via in-situ transesterification then and handles with cyclopropylamine and transforms the cost title compound.Handle this free alkali with the saturated solution of 50% oxalic acid in ether.Collect the gained white solid via filtering, obtained this title compound (41mg, 4.2%).MS?APCI+ve? m/z?390[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)δ7.96(d，1H)，7.49(d，1H)，7.45-7.39(m，3H)，7.39-7.31(m，2H)，5.82-5.74(m，1H)，3.16-3.00(m，2H)，2.74-2.64(m，1H)，2.38-2.25(m，1H)，2.24-2.11(m，1H)，0.79-0.64(m，4H).
Embodiment 294-bromo-2-{[(1R)-and 3-(cyclopropyl amino)-1-(3-furyl) propyl group] the oxygen base }-5-fluorine benzonitrile oxalate
This compound makes like this: by the method for embodiment 25, at first use (R)-α-(2-chloroethyl) phenylcarbinol and 4-bromo-2,5-difluoro benzonitrile changes into iodine compound via in-situ transesterification then and handles with cyclopropylamine and transforms the cost title compound.Handle this free alkali with the saturated solution of 50% oxalic acid in ether.Collect the gained white solid via filtering, obtained this title compound (41mg, 4.2%).MS?APCI+ve? m/z?380[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.95(d，1H)，7.81(s，1H)，7.71-7.66(m，2H)，6.53(s，1H)，5.77-5.69(m，1H)，3.15-2.99(m，2H)，2.73-2.65(m，1H)，2.41-2.29(m，1H)，2.25-2.12(m，1H)，0.80-0.67(m，4H).
Embodiment 304-bromo-2-{[(1R)-and 3-(cyclopropyl amino)-1-(3-thienyl) propyl group] the oxygen base }-5-fluorine benzonitrile oxalate
This compound makes like this: by the method for embodiment 25, at first use (R)-α-(2-chloroethyl)-3-thiophen(e)alcohol and 4-bromo-2,5-difluoro benzonitrile changes into iodine compound via in-situ transesterification then and handles with cyclopropylamine and transforms the cost title compound.Handle this free alkali with the saturated solution of 50% oxalic acid in ether.Collect the gained white solid via filtering, obtained this title compound (47mg, 4.8%).MS?APCI+ve? m/z?396[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.95(d，1H)，7.63-7.57(m，3H)，7.14(d，1H)，5.83(t，1H)，3.14-3.00(m，2H)，2.73-2.65(m，1H)，2.40-2.30(m，1H)，2.26-2.15(m，1H)，0.78-0.67(m，4H).
Embodiment 314-chloro-5-fluoro-2-((1R)-and the 3-[(3-hydroxypropyl) amino]-the 1-phenyl propyl } the oxygen base) the benzonitrile oxalate
By the method for embodiment 25, but (150mg 2mmol) handles the intermediate iodine compound, has obtained this title compound (67mg, 7.4%) with 3-amino-1-propyl alcohol.MS?APCI+ve m/z?363/365[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.03(d，1H)，7.43(m，4H)，7.40(d，1H)，7.35(m，1H)，5.81-5.74(m，1H)，3.47(t，2H)，3.13-3.00(m，2H)，3.02-2.95(m，2H)，2.39-2.27(m，1H)，2.23-2.12(m，1H)，1.77-1.67(m，2H).
Embodiment 324-chloro-5-fluoro-2-[[(1R)-and 1-(3-furyl)-3-(3-hydroxypropyl) amino] propyl group] the oxygen base } the benzonitrile oxalate
By the method for embodiment 26, but (150mg 2mmol) handles the intermediate iodine compound, has obtained this title compound (49mg, 5.5%) with 3-amino-1-propyl alcohol.MS?APCI+ve? m/z?353/355[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.01(d，1H)，7.81(s，1H)，7.70-7.69(m，1H)，7.59(d，1H)，6.54-6.53(m，1H)，5.76-571(m，1H)，3.48(t，2H)，3.07-3.01(m，2H)，3.02-2.97(m，2H)，2.41-2.31(m，1H)，2.26-2.15(m，1H)，1.78-1.69(m，2H).
Embodiment 334-chloro-5-fluoro-2-{[(1R)-and the 3-[(3-hydroxypropyl) amino]-1-(3-thienyl) propyl group] the oxygen base } the benzonitrile oxalate
By the method for embodiment 27, but (150mg 2mmol) handles the intermediate iodine compound, has obtained this title compound (74mg, 8%) with 3-amino-1-propyl alcohol.MS?APCI+ve? m/z?369[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.02(d，1H)，7.62-7.60(m，2H)，7.50(d，1H)，7.16-7.13(m，1H)，5.87-5.82(m，1H)，3.47(t，2H)，3.09-3.02(m，2H)，3.02-2.96(m，2H)，2.42-2.32(m，1H)，2.27-2.16(m，1H)，1.77-1.68(m，2H).
Embodiment 344-bromo-5-fluoro-2-((1R)-and the 3-[(3-hydroxypropyl) amino]-the 1-phenyl propyl } the oxygen base) the benzonitrile oxalate
By the method for embodiment 28, but (150mg 2mmol) handles the intermediate iodine compound, has obtained this title compound (25mg, 2.5%) with 3-amino-1-propyl alcohol.MS?APCI+ve? m/z?407/409[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.97(d，1H)，7.49(d，1H)，7.45-7.40(m，4H)，7.39-7.32(m，2H)，5.80-5.74(m，1H)，3.47(t，2H)，3.13-3.03(m，2H)，3.02-2.96(m，2H)，2.38-2.28(m，1H)，2.23-2.14(m，m)，1.77-1.68(m，2H).
Embodiment 35
By the method for embodiment 29, but (150mg 2mmol) handles the intermediate iodine compound, has obtained this title compound (42mg, 4.3%) with 3-amino-1-propyl alcohol.MS?APCI+ve m/z399/401[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.94(d，1H)，7.81-7.80(m，1H)，7.71-7.67(m，2H)，6.54-6.52(m，1H)，5.74(t，1H)，3.48(t，2H)，3.10-3.01(m，2H)，3.02-2.97(m，2H)，2.42-2.31(m，1H)，2.26-2.16(m，1H)，1.78-1.70(m，2H).
Embodiment 364-bromo-5-fluoro-2-{[(1R)-and the 3-[(3-hydroxypropyl) amino]-1-(3 thienyl) propyl group] the oxygen base } the benzonitrile oxalate
By the method for embodiment 30, but (150mg 2mmol) handles the intermediate iodine compound, has obtained this title compound (42mg, 4.3%) with 3-amino-1-propyl alcohol.MS?APCI+ve? m/z?414/416[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.95(d，1H)，7.64-7.57(H，3H)，7.16-7.12(m，1H)，5.88-5.81(m，1H)，3.47(t，2H)，3.10-3.01(m，2H)，3.02-2.97(m，2H)，2.42-2.30(m，1H)，2.28-2.16(m，1H)，1.78-1.68(m，2H).
Embodiment 372-[[(1R)-and 3-amino-1-phenyl propyl] the oxygen base]-a) (R)-α-(2-azido-ethyl) phenylcarbinol of 4-(trifluoromethyl) benzonitrile oxalate
With (R)-α-(2-chloroethyl) phenylcarbinol (0.73g, 4.3mmol) and sodiumazide (417mg, 1.5 equivalents) stirs in DMSO (3ml) and 40 ℃ the heating 1.5 hours.Water (50ml) dilutes this reaction mixture, and product is extracted in the ethyl acetate (2 * 75ml).With the extraction liquid drying (using sal epsom) that merges, and be concentrated into oily matter.Purifying on silica gel with 50% ether/isohexane wash-out, has obtained trinitride, is colorless oil (0.6g, 79%). 1H NMR 300MHz (CDCl 3) 7.61-7.27 (5H, m), 4.88-4.82 (1H, m), 3.55-3.35 (2H, m), 2.11-1.89 (2H, m) .b) 2-[[(1R)-3-azido--1-phenyl propyl] the oxygen base]-4-(trifluoromethyl) benzonitrile
Under nitrogen atmosphere, (0.49g, 2.77mmol) (0.523g, 2.77mmol) (60% dispersion liquid, 111mg 2.77mmol) handle the mixture in anhydrous tetrahydro furan (30ml) with sodium hydride with 2-fluoro-4-(trifluoromethyl) benzonitrile with azido-alcohol 37 (a).With this mixture stirring and 60 ℃ of heating 1.5 hours, water (150ml) quenching is handled then.Product is extracted into ether (in 2 * 100ml).With the combining extraction liquid dried over mgso, filter and be concentrated into oily matter.This crude product of purifying on silica gel with 10% ether/isohexane wash-out, has obtained this title compound, is colorless oil (770mg, 80%).MS APCI+ve m/ z 319[(M+H-28)] 2-[[(1R .c))-and 3-amino-1-phenyl propyl] the oxygen base]-4-(trifluoromethyl) benzonitrile oxalate
With 2-[[(1R)-3-azido--1-phenyl propyl] the oxygen base]-4-(trifluoromethyl) benzonitrile (770mg, 2.2mmol) handle with triphenylphosphine (1.5 equivalent) and water (0.5ml) by the solution in tetrahydrofuran (THF) (50ml).This mixture stirring at room 24 hours, is concentrated into oily matter then.Purifying amine crude product is used eluent ethyl acetate on silica gel, uses the methanol solution/methylene dichloride wash-out of 10%7N ammonia then.Use the ethanolic soln of 1 equivalent oxalic acid that gained oily matter is changed into oxalate, obtained this title compound, be colorless solid (510mg, 56%).MS?APCI+ve? m/z?321[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.0(1H，d)，7.44-7.31(7H，m)，5.93(1H，dd)，3.04-2.9(2H，m)，2.4-2.1(2H，m).
Embodiment 382-[[(1R)-and 3-amino-1-phenyl propyl] the oxygen base]-a) 2-[[(1R of 4-benzyl chloride nitrile)-3-azido--1-phenyl propyl] the oxygen base]-4-benzyl chloride nitrile
The book title compound is the method by embodiment 37 (b), but is to use 4-chloro-2-fluorine benzonitrile to make. 1H NMR 400MHz (CDCl 3) 7.48-7.32 (6H, m), 6.95 (1H, dd), 6.79 (1H, d), 5.34 (1H, dd), 3.69-3.63 (1H, m), 3.5-3.44 (1H, m), 2.39-2.32 (1H, m), 2.14-2.05 (1H, m) .b) 2-[[(1R)-3-amino-1-phenyl propyl] the oxygen base]-4-benzyl chloride nitrile oxalate
The book title compound is the method by embodiment 37 (c), but is to use 2-[[(1R)-3-azido--1-phenyl propyl] the oxygen base]-4-benzyl chloride nitrile makes.MS?APCI+ve? m/z?287/9[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.79(1H，d)，7.46-7.31(5H，m)，7.19-7.14(2H，m)，5.81(1H，dd)，3.01-2.74(2H，m)，2.35-2.08(2H，m).
Embodiment 394-chloro-5-fluoro-2-[[(1R)-and 3-(methylamino)-1-phenyl propyl] the oxygen base] a) [(3R)-3-(5-chloro-2-cyano group-4-fluorophenoxy)-3-phenyl propyl] methyl carbamic acid 1 of benzonitrile, 1-dimethyl ethyl ester
The book title compound is the method by embodiment 3 (b), uses 4-chloro-2,5 difluoro benzonitriles, and make as solvent with dimethyl formamide.MS APCI+ve m/ z 319/21[(M-(C 4H 9)+H) +] .b) 4-chloro-5-fluoro-2-[[(1R)-3-(methylamino)-1-phenyl propyl] the oxygen base] the benzonitrile oxalate
Will [(3R)-and 3-(5-chloro-2-cyano group-4-fluorophenoxy)-3-phenyl propyl] (220mg 0.525mmol) stirred 20 minutes in 4N hydrogenchloride De dioxane solution (20ml) methyl carbamic acid 1,1 dimethyl ethyl ester.Hydrochloride is applied on the silicagel column, and with the methanol solution/methylene dichloride wash-out of 10%7N ammonia.Ethanolic soln with 1 equivalent oxalic acid changes into oxalate with this free alkali then.Obtained this title compound, be colorless solid (175mg, 82%).MS?APCI+ve? m/z?319/321[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.02(1H，d)，7.43-7.31(6H，m)，5.79(1H，dd)，3.09-2.93(2H，m)，2.53(3H，s)，2.4-2.1(2H，m).
Embodiment 402-[[(1R)-and 3-amino-1-phenyl propyl] the oxygen base]-a) 2-[[(1R of 4-chloro-5-fluorine benzonitrile oxalate)-3-azido--1-phenyl propyl] the oxygen base]-4-chloro-5-fluorine benzonitrile
Under nitrogen atmosphere, (8g, 0.045mol) (7.83g, 0.045mol) (60% dispersion liquid, 1.81g 0.045mol) handle the mixture in anhydrous dimethyl formamide (70ml) with sodium hydride with 4-chloro-2,5 difluoro benzonitriles with azido-alcohol 37 (a).With this mixture stirring and 60 ℃ of heating 2 hours, water (500ml) quenching is handled then.Product is extracted in the ether (2 * 300ml).With the extraction liquid dried over mgso that merges, filter and be concentrated into oily matter.Purifying crude product on silica gel with 20% ether/isohexane wash-out, has obtained this title compound, is colorless oil (9.4g, 80%). 1H NMR 300MHz (CDCl 3) 7.43-7.3 (6H, m), 6.84 (1H, dd), 5.29 (1H, dd), 3.7-3.42 (2H, m), 2.4-2.04 (2H, m) .b) 2-[[(1R)-3-amino-1-phenyl propyl] the oxygen base]-4-chloro-5-fluorine benzonitrile oxalate
According to being similar to the middle method of describing of embodiment 37 (c) with 2-[[(1R)-3-azido--1-phenyl propyl] the oxygen base]-4-chloro-5-fluorine benzonitrile (embodiment 40 (a)) reduction.MS?APCI+ve? m/z?305/7[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.01(1H，d)，7.44-7.31(6H，m)，5.78(1H，dd)，2.91-2.81(2H，m)，2.28-2.05(2H，m).
Embodiment 41 γ-[5-chloro-2-(trifluoromethyl) phenoxy group]-Corvitin hydrochloride
This title compound is the method by embodiment 3 (b), uses racemize (3-hydroxyl-3-phenyl propyl) carboxylamine 1,1-dimethyl ethyl ester and 2, and 4-two chloro-1-(trifluoromethyl) benzene make, and have obtained the 70mg product, are colorless solid.MS?APCI+ve? m/z?344/6[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.93-8.79(m，2H)，7.65(d，1H)，7.45-7.39(m，4H)，7.38-7.30(m，1H)，7.15(s，1H)，7.13(d，1H)，5.88(dd，1H)，3.01-2.90(m，2H)，2.55(s，3H)，2.37-2.12(m，2H).
Embodiment 422-[[(1R)-and 3-(methylamino)-1-phenyl propyl] the oxygen base]-4-(trifluoromethyl) benzonitrile hydrochloride
This title compound is the method by embodiment 3 (b), uses 2-fluoro-4-(trifluoromethyl) benzonitrile to make, and has obtained the 290mg product, is white solid.MS?APCI+ve? m/z?335[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)9.12-8.99(m，2H)，8.00(d，1H)，7.50-7.30(m，7H)，6.06(dd，1H)，3.10-2.96(m，2H)，2.57(s，3H)，2.46-2.20(m，2H).
Embodiment 434-chloro-5-fluoro-2-[[(1R)-and 3-[[(5-methylpyrazine base) methyl] amino]-the 1-phenyl propyl] the oxygen base] a) 4-chloro-2-[[(1R of benzonitrile dihydrochloride)-3-ammonia-1-phenyl propyl] the oxygen base]-5-fluorine benzonitrile
With 4-chloro-2,5-difluoro benzonitrile (1.0g, 5.8mmol) and S-α-(2-chloroethyl) phenylcarbinol (1.0g 5.86mmol) is dissolved in the dimethyl formamide (10ml), and with 5 minutes the dropping 60% NaH (350mg, 8.7mmol).This mixture was stirred 2 hours, and the water quenching is handled, and uses ethyl acetate extraction.Wash extraction liquid with water (* 3), use dried over mgso, filter and evaporation.By purified by flash chromatography (5% ethyl acetate/hexane), obtained 1.8g (96%) product, be colorless oil. 1H NMR 300MHz (CDCl 3) 7.44-7.32 (m, 5H), 7.31 (d, 1H), 6.87 (d, 1H), 5.44 (dd, 1H), 3.93-3.82 (m, 1H), 3.67-3.57 (m, 1H), 2.64-2.51 (m, 1H), 2.31-2.18 (m, 1H) .b) 4-chloro-5-fluoro-2-{[(1R)-3-iodo-1-phenyl propyl] the oxygen base) benzonitrile
With 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base)-5-fluorine benzonitrile (1.8g, 5.6mmol) and sodium iodide (12.8g 100mmol) is dissolved in the acetone (50ml), and reflux 24 hours.With this reaction mixture cooling, filter and evaporation.This semi-solid residue is dissolved in the toluene, filters once more and evaporate, obtained the 2.3g crude product, be yellow oil.This product is directly used in next step without purifying.C) 4-chloro-5-fluoro-2-[[(1R)-and 3-[[(5-methylpyrazine base) methyl] amino]-the 1-phenyl propyl] the oxygen base] the benzonitrile dihydrochloride
With 4-chloro-5-fluoro-2-{[(1R)-3-iodo-1-phenyl propyl] the oxygen base) benzonitrile (200mg, 0.48mmol), 5-methyl-2-pyrazine methylamine (120mg, 0.96mmol) and triethylamine (335 μ l 2.4mmol) stirred in DMS0 (5ml) 48 hours.This mixture is washed with water, and by chromatography purification (5% 1M ammonia-ethanol/methylene).With the elutriant evaporation, with resistates 4M hydrogenchloride De dioxane solution (5ml) wash-out.With solvent evaporation, with methylbenzene azeotropic 2 times, and, obtained required product with the ether development, be white solid.MS?APCI+ve? m/z?411[(M+H) +]. 1H?NMR400?MHz(d 6-DMSO)8.71(s，1H)，8.58(s，1H)，8.01(d，1H)，7.49(d，1H)，7.46-7.30(m，5H)，5.96(dd，1H)，4.36(t，2H)，3.20-3.02(m，2H)，2.53(s，3H)，2.52-2.28(m，2H).
Embodiment 444-chloro-5-fluoro-2-[[(1R)-and 3-[(1H-imidazoles-2-ylmethyl) amino]-the 1-phenyl propyl] the oxygen base] the benzonitrile dihydrochloride
This title compound is the method by embodiment 43 (c), uses 1H-imidazoles-2-methylamine to make, and has obtained this title compound, is white solid.MS?APCI+ve? m/z?385[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.01(d，1H)，7.72(s，2H)，7.51(d，2H)，7.49-7.32(m，5H)，6.00(dd，1H)，4.54(s，2H)，3.26-3.12(m，2H)，2.50-2.25(m，2H).
Embodiment 452-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-a) 2-[[(1R of 4-(trifluoromethyl)-benzonitrile fumarate)-3-azido--1-(3-isoxazolyl) propyl group] the oxygen base]-4-(trifluoromethyl) benzonitrile
Use the method for describing among the embodiment 93 (b),, obtained product, be gum, it is directly used in next step embodiment 93 (a) product (0.17g) and 4-(trifluoromethyl)-2-fluoro-benzonitrile (0.3g) reaction.B) 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-(trifluoromethyl) benzonitrile fumarate
Method with step (a) product carries out description among the embodiment 90 (b) has obtained product, is solid (0.1g).MS?APCI+ve? m/z?312[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.99(1H，d)，8.03(1H，d)，7.60(1H，s)，7.50(1H，d)，6.74(1H，d)，6.43(2H，s)，6.24-6.15(1H，m)，2.98(2H，dd)，2.48-235(1H，m)，2.34-2.21(1H，m).
Embodiment 464-chloro-2-[[(1R)-and 3-[[2-(dimethylamino) ethyl] amino]-the 1-phenyl propyl] the oxygen base]-5-fluorine benzonitrile dihydrochloride
This title compound is the method by embodiment 43 (c), uses N 1, N 1-dimethyl-1 makes, and has obtained product, is white solid.MS?APCI+ve? m/z?376[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.02(d，1H)，7.52(d，1H)，7.48-7.32(m，5H)，5.95(dd，3H)，3.47-3.39(m，2H)，3.39-3.30(m，2H)，3.19-3.03(m，2H)，2.83(s，6H)，2.47-2.22(m，2H).
Embodiment 474-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(4-morpholinyl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] the benzonitrile dihydrochloride
This title compound is the method by embodiment 43 (c), uses 4-morpholine ethamine to make, and has obtained product, is white solid.MS?APCI+ve? m/z?418[[M+H] +]. 1H?NMR?400MHz(d 6-DMSO)9.75-9.50(m，2H)，8.02(d，1H)，7.51(d，1H)，7.48-7.32(m，5H)，5.95(dd，1H)，4.07-3.91(m，2H)，3.86-3.70(m，2H)，3.61-3.34(m，6H)，3.22-3.01(m，4H)，2.50-2.20(m，2H).
Embodiment 484-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(1H-imidazoles-1-yl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] the benzonitrile dihydrochloride
This title compound is the method by embodiment 43 (c), uses 1H-imidazoles-1-ethamine to make, and has obtained product, is white solid.MS?APCI+ve? m/z?399[(M+H) -]. 1H?NMR?300MHz(d 6-DMSO)9.17-9.12(m，1H)，8.01(d，1H)，7.82-7.78(m，1H)，7.69-7.65(m，1H)，7.53(d，1H)，7.49-7.30(m，5H)，5.98(dd，1H)，4.61(t，2H)，3.50(t，2H)，3.13-2.99(m，2H)，2.45-2.22(m，2H).
Embodiment 494-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(1H-imidazol-4 yl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] the benzonitrile dihydrochloride
This title compound is the method by embodiment 43 (c), uses 1H-imidazoles-4-ethamine to make, and has obtained product, is white solid.MS?APCI+ve? m/z399[(M+H) -].
Embodiment 504-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-the 1-phenyl propyl] the oxygen base] the benzonitrile hydrochloride
This title compound is the method by embodiment 43 (c), uses the 2-monoethanolamine to make, and has obtained product, is white solid.MS?APCI+ve? m/z?349[(M+H) -]. 1H?NMR?400MHz(d 6-DMSO)9.10-8.90(m，2H)，8.02(d，1H)，7.49(d，1H)，7.47-7.39(m，4H)，7.38-7.32(m，1H)，5.91(dd，1H)，5.26(t，2H)，3.67(q，2H)，3.13-2.96(m，2H)，2.46-2.21(m，2H).
Embodiment 512-[[(1R)-and the 3-[(2-amino-ethyl) amino]-the 1-phenyl propyl] the oxygen base]-4-chloro-5-fluorine benzonitrile dihydrochloride
This title compound is the method by embodiment 43 (c), uses 1 to make, and has obtained product, is white solid.MS?APCI+ve? m/z?348[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.01(d，1H)，7.51(d，1H)，7.48-7.32(m，5H)，5.98(dd，1H)，3.37-3.30(m，2H)，3.26-3.16(m，2H)，3.13-3.04(m，2H)，2.48-2.20(m，2H).
Embodiment 524-chloro-5-fluoro-2-[[(1R)-and 1-phenyl-3-[(3,3, the 3-trifluoro propyl) amino] propyl group] the oxygen base] the benzonitrile trifluoroacetate
With 2-[[(1R)-3-amino-1-phenyl propyl] the oxygen base]-4-chloro-5-fluorine benzonitrile (300mg, 0.99mmol) and 3,3,3-trifluoro propionic aldehyde (123mg, 1.2mmol) be dissolved in the methylene dichloride (10ml), add 4 dust molecular sieves, add sodium triacetoxy borohydride (320mg then, 1.5mmol), and stirred 20 hours.This reaction mixture is washed with saturated sodium bicarbonate aqueous solution, use dried over mgso, filter and evaporation.By reverse-phase chromatography purifying resistates (0.1% trifluoroacetic acid aqueous solution/methyl alcohol), obtained the 280mg product, be white solid.MS?APCI+ve? m/z?401[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.99-8.82(m，2H)，8.04(d，5H)，7.48-7.30(m，2H)，5.78(dd，1H)，3.26(t，2H)，3.21-3.03(m，2H)，2.79-2.61(m，2H)，2.43-2.13(m，2H).
Embodiment 532-{[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base }-a) [3-oxo-3-(2-thiazolyl) propyl group] carboxylamine 1 of 4-benzyl chloride nitrile hydrochloride, 1-dimethyl ethyl ester
Under-78 ℃, nitrogen atmosphere, with 30 fens clockwise 2-bromo thiazole (5.035g, 30.7mmol) add the hexane solution (1.6M of n-Butyl Lithium in the solution in anhydrous tetrahydro furan (125ml), 17.6ml, 28.2mmol), then with 30 minutes adding [3-(methoxymethyl amino)-3-oxopropyl] carboxylamines 1,1-dimethyl ethyl ester (2.976g, 12.8mmol) solution in anhydrous tetrahydro furan (30ml).This reaction mixture is warmed to 0 ℃, handles with the saturated ammonium chloride quenching, and with ethyl acetate extraction (3 * 100ml).With the extraction liquid water that merges (3 * 50ml) and saturated brine solution (1 * 100ml) washing, drying (using sal epsom), and vacuum concentration have obtained thick orange.By purification by flash chromatography (silicon-dioxide, the mixture of 25% ethyl acetate in isohexane), obtained 2.2g light yellow oil (67%).MS APCI+ve m/ z 201 ([(M (C 4H 9)+H) +]. 1H NMR 300MHz (CDCl 3) 8.01 (1H, m), 7.69 (1H, m), 5.05 (1H, br s), 3.57 (2H, q), 3.39 (2H, t), 1.46 (9H, s) .b) [(3R)-and 3-hydroxyl-3-(2-thiazolyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester
Under-10 ℃, nitrogen atmosphere, to (S)-3-methyl-CBS-oxa-azepine boron heterocyclic pentene (1M toluene solution, 0.43ml) (tetrahydrofuran (THF) of 1M 2.58ml), and stirred 15 minutes at-10 ℃ to add borine-tetrahydrofuran complex in the solution in anhydrous tetrahydro furan (30ml).With dripping [3-oxo-3-(2-thiazolyl) propyl group] carboxylamine 1 in 45 minutes, and 1-dimethyl ethyl ester (1.1g, the 4.3mmol) solution in anhydrous tetrahydro furan (20ml), and the gained mixture is warmed to room temperature with 16 hours.Add methyl alcohol (10ml), and with this mixture in stirring at room 15 minutes, removal of solvent under reduced pressure then.Add methyl alcohol (10ml) again, and the decompression remove, obtained thick yellow oil.By purification by flash chromatography (silicon-dioxide, the mixture of 25-100% ethyl acetate in isohexane), obtained the clarifying gum of 0.75g (67%).MS APCI+ve m/ z 259[(M ÷ H) +]. 1H NMR 300MHz (CDCl 3) 7.72 (1H, d), 7.29 (1H, d), 5.06-5.02 (1H, m), 4.92 (1H, br s), 4.71 (1H, s), 3.70-3.58 (1H, m), 3.25-3.16 (1H, m), 2.24 (1H, m), and 1.93-1.87 (1H, m), (1.44 9H, s) .c) [(3R)-3-(5-chloro-2-cyano-benzene oxygen)-3-(2-thiazolyl) propyl group] carboxylamine 1,1 dimethyl ethyl ester
To 4-chloro-2-fluorine benzonitrile (156mg, 1mmol) and [(3R)-3-hydroxyl-3-(2-thiazolyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester (258mg, 1mmol) add sodium hydride (60% oily dispersion liquid in the solution in anhydrous dimethyl formamide (3ml), 40mg, 1mmol), and with this mixture stirring at room 16 hours.Should react with the poly-deepfreeze of methyl alcohol, and between ethyl acetate and water, distribute.(3 * 25ml) and the saturated brine solution washing, dry (using sal epsom), and vacuum concentration have obtained thick yellow gum with the extraction liquid water that merges.By purification by flash chromatography (silicon-dioxide, the mixture of 15% ethyl acetate in isohexane), obtained 345mg white solid (86%).MS APCI+ve m/ z 394/396[(M+H) +]. 1H NMR 300MHz (CDCl 3) 7.79 (1H, d), 7.49 (1H, d), 7.38 (1H, d), 7.06 (1H, d), 7.02 (1H, dd), 5.72 (1H, dd), 4.80 (1H, bd s), 3.56-3.20 (2H, m), 2.50-2.20 (2H, m), 1.44 (9H, s) .d) 2-{[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base }-4-benzyl chloride nitrile hydrochloride
To [(3R)-3-(5-chloro-2-cyano-benzene oxygen)-3-(2-thiazolyl) propyl group]-carboxylamine 1,1-dimethyl ethyl ester (140mg, 0.36mmol) add 4M HCl De dioxane solution (1ml) in the solution in no Shui diox (3ml), and with this mixture stirring at room 16 hours.Collecting precipitation, with the ethyl acetate washing, and vacuum-drying, obtained 106mg white solid (90%).MS?APCI+ve? m/z?294/296[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)δppm：8.16(3H，br?s)，7.90-7.83(3H，m)，7.52(1H，d)，7.26(1H，dd)，6.31(1H，dd)，3.10-2.96(2H，m)，2.48-2.38(2H，m).
Embodiment 544-chloro-2-{[(1R)-and 3-(methylamino)-1-(2-thiazolyl) propyl group] the oxygen base } a) [(3R)-3-(5-chloro-2-cyano-benzene oxygen)-3-(2-thiazolyl) propyl group] methyl carbamic acid 1 of benzonitrile hydrochloride, 1-dimethyl ethyl ester
To [(3R)-3-(5-chloro-2-cyano-benzene oxygen)-3-(2-thiazolyl) propyl group]-carboxylamine 1,1-dimethyl ethyl ester (200mg, 0.51mmol) add sodium hydride (56mg in the solution in anhydrous tetrahydro furan (10ml), 60% oil suspension, 1.41mmol), and stirring at room 15 minutes.The adding methyl iodide (1.325g, 0.58ml, 4.7mmol).This was reflected at stirring at room 18 hours, handles with the saturated ammonium chloride solution quenching, and between ethyl acetate and water, distribute.(3 * 25ml) and the saturated brine solution washing, dry (using sal epsom), and vacuum concentration have obtained thick yellow gum with the extraction liquid water that merges.By purification by flash chromatography (silicon-dioxide, the mixture of 25% ethyl acetate in isohexane), obtained the opaque oily matter of 175mg (98%).MS APCI+ve m/ z 408/410[(M+H) +]. 1H NMR 300MHz (CDCl 3) 7.79 (1H, d), 7.49 (1H, d), 7.37 (1H, d), 7.07 (1H, s), 7.01 (1H, d), 5.68-5.63 (1H, m), 3.70-3.56 (1H, m), 3.43-3.33 (1H, m), 2.88 (3H, s), 2.45-2.28 (2H, m), 1.44 (9H, s) .b) 4-chloro-2-([(1R)-3-(methylamino)-1-(2-thiazolyl) propyl group] oxygen base] the benzonitrile hydrochloride
This title compound is to use the method identical with embodiment 53 (d) to make, and has obtained 175mg white solid (99%).MS?APCI+ve? m/z?308/310[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.90-7.83(3H，m)，7.56-7.51(1H，m)，7.27(1H，d)，6.35-6.25(1H，m)，3.29(3H，s)，3.09(2H，t)，2.60-2.54(2H，m).
Embodiment 55 (R)-γ-(2, the 5-dichlorophenoxy)-2-thiazole propylamin hydrochloride is [(3S)-3-hydroxyl-3-(2-thiazolyl) propyl group] carboxylamine 1 a), 1-dimethyl ethyl ester
Under-10 ℃, nitrogen atmosphere, to (R)-3-methyl-CBS-oxa-azepine boron heterocyclic pentene (1M toluene solution, 0.43ml) (the 1M tetrahydrofuran solution 2.58ml), and stirred 15 minutes at-10 ℃ to add borine-tetrahydrofuran complex in the solution in anhydrous tetrahydro furan (30ml).With dripping [3-oxo-3-(2-thiazolyl) propyl group] carboxylamine 1 in 45 minutes, and 1-dimethyl ethyl ester (1.1g, the 4.3mmol) solution in anhydrous tetrahydro furan (20ml), and the gained mixture is warmed to room temperature with 16 hours.Add methyl alcohol (10ml), and with this mixture in stirring at room 15 minutes, removal of solvent under reduced pressure then.Add methyl alcohol (10ml) again, and the decompression remove, obtained thick yellow oil.By purification by flash chromatography (silicon-dioxide, the mixture of 25-100% ethyl acetate in isohexane), obtained the clarifying gum of 0.74g (67%).MS APCI+ve m/ z 259[(M+H) +]. 1H NMR 300MHz (CDCl 3) 7.72 (1H, d), 7.29 (1H, d), 5.06-5.02 (1H, m), 4.95 (1H, bd s), 4.75 (1H, s), 3.70-3.58 (1H, m), 3.25-3.16 (1H, m), 2.24-2.16 (1H, m), 1.93-1.87 (1H, m), 1.44 (9H, s) .b) [(3R)-and 3-(2, the 5-dichlorophenoxy)-3-(2-thiazolyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester
Under 0 ℃, nitrogen atmosphere, with 5 fens clockwise 2,5-chlorophenesic acid (163mg, 1mmol), [(3S)-and 3-hydroxyl-3-(2-thiazolyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester (258mg, 1mmol) and triphenylphosphine (315mg 1.2mmol) drips diisopropyl azodiformate (243mg in the solution in anhydrous tetrahydro furan (30ml), 0.24ml, 1.2mmol).This mixture stirring at room 16 hours, should be reacted vacuum concentration then, obtained thick yellow gum.By purification by flash chromatography (silicon-dioxide, the mixture of 15% ethyl acetate in isohexane), obtained the clarifying oily matter of 245mg (63%).MS APCI+ve m/ z 403/405/407[(M+H) +]. 1H NMR 300MHz (CDCl 3) 7.79 (1H, d), 7.35 (1H, d), 7.29 (1H, d), 6.93 (1H, d), 6.90 (1H, dd), 5.66 (1H, dd), 5.03 (1H, bd s), 3.50-320 (2H, m), 2.45-2.25 (2H, m), 1.43 (9H, s) .c) (R)-γ-(2, the 5-dichlorophenoxy)-2-thiazole propylamin hydrochloride
This title compound is to use the method for embodiment 53 (d) to make, and has obtained 144mg white solid (70%).MS?APCI+ve? m/z?303/305[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.95(3H，m)，7.78(1H，d)，7.56(1H，d)，7.53(1H，d)，7.34(1H，dd)，5.36-5.30(1H，m)，3.08-2.84(2H，m)，2.46-2.26(2H，m).
Embodiment 562-[3-amino-1-(2-oxazolyl) propoxy-]-a) 3-chloro-1-(2-oxazolyl)-1-propantheline of 4-benzyl chloride nitrile oxalate
(2.93g 42.5mmol) drips n-Butyl Lithium (17ml 2.5M hexane solution) to ， in the solution in tetrahydrofuran (THF) (150ml), and with this solution stirring 20 minutes Xiang oxazole under-70 ℃, nitrogen atmosphere.Add zinc chloride (84.9ml 1M diethyl ether solution), this solution is warmed to 0 ℃ with 45 minutes.Adding solid cuprous iodide (8.09g, 42.5mmol), after 10 minutes, adding 3-chlorpromazine chloride (8.38ml, 87.8mmol).After 1 hour, add ethyl acetate and aqueous ammonium chloride solution.Isolate organic layer, use aqueous ammonium chloride solution, water and salt water washing successively.With this solution drying (using sodium sulfate), and evaporation, obtained the 15.5g crude product, be red oil.This mixture need not be further purified direct use. 1H NMR 300MHz (CDCl 3) 7.86 (1H, s), 7.36 (1H, s), 3.93 (2H, t), 3.57 (2H, m) .b) R-α-(2-azido-ethyl)-2-oxazole methyl alcohol
Under nitrogen atmosphere, (S)-2-methyl-CBS-oxa-azepine boron heterocyclic pentene (0.72ml 1M toluene solution) is added in the tetrahydrofuran (THF) (5ml), and this solution is cooled to-5 ℃.Drip borine-tetrahydrofuran complex (7.2ml 1M tetrahydrofuran solution), and with this solution stirring 10 minutes.Drip the solution of embodiment 56 (a) crude product (about 7.24mmol) in tetrahydrofuran (THF) (7ml), with 16 hours with this sluggish be warmed to 0 ℃.Add methyl alcohol (20ml) carefully, and vacuum is removed volatile matter.Carry out adding for 2 times methyl alcohol/solvent evaporation circulation again.By the purified by flash chromatography resistates, use 10-40% ethyl acetate/isohexane as eluent, obtained the 724mg colorless oil.Oily matter is placed methyl-sulphoxide (5ml), add solid sodiumazide (450mg), and this is reflected at 65 ℃ of heating 16 hours.After being cooled to room temperature, add entry, with ether with this solution extraction 3 times (3 *).With the organic extract liquid drying (using sodium sulfate) that merges, solvent removed in vacuo has obtained 490mg book title compound, is orange, need not be further purified direct use. 1H NMR 300MHz (CDCl 3) 7.65 (1H, s), 7.10 (1H, s), 4.97 (1H, dt), 3.63-3.47 (2H, m), 3.05 (1H, bs), 2.28-2.07 (2H, m) .c) 2-[3-amino-1-(2-oxazolyl) propoxy-]-4-benzyl chloride nitrile oxalate
In the solution of embodiment 56 (b) product (160mg) in dimethyl formamide (2ml), add sodium hydride (the mineral oil dispersion liquid of 76mg 60%), and should react and stir 1 hour.Add solid 4-chloro-2-fluoro-benzonitrile (296mg), and should react and stir 2 hours.Add entry, and with this solution of extracted with diethyl ether.Isolate organic extract liquid, dry (using sodium sulfate), and solvent removed in vacuo.Resistates is placed tetrahydrofuran (THF) (4m1), and add triphenylphosphine (283mg).After 5 minutes, add entry (1ml), and should react and stir 16 hours.Add entry (2ml) again, this is reflected at 55 ℃ stirred 3 hours, then stirring at room 48 hours.This reaction is poured in ethyl acetate/1N aqueous sodium hydroxide solution.Isolate organic extract liquid, dry (using sodium sulfate), and solvent removed in vacuo.By the RP-HPLC purifying, obtained this title product (20mg) of free alkali form, be white solid.This product is placed ether/methylene dichloride (1: 1), add the solution of oxalic acid (15mg) in ether (1ml).Filter out the gained solid, and vacuum-drying, obtained this title product of 4mg, be the water absorbability white solid.MS?APCI+ve m/z278[(M+H) +]. 1H?NMR?400MHz(d 4-MeOH)7.87(1H，s)，7.66(1H，d)，7.34(1H，s)，7.22(1H，d)，7.17(1H，s)，3.21(1H，m)，3.10(1H，m)，2.73(1H，ddd)，2.46(1H，ddd).
Embodiment 57 γ-(2, the 5-dichlorophenoxy)-2-oxazole propanamine oxalate
This title compound be according to the method that is similar to embodiment 56 (c) by embodiment 56 (b) product and 1,4-two chloro-2-fluorobenzene make.Carry out last purifying by recrystallization (with 2-propyl alcohol/methanol), obtained beige solid.MS?APCI+ve m/z287[(M+H) +]. 1H?NMR?400MHz(d 4-MeOH)7.96(1H，s)，7.37(1H，d)，7.23(1H，s)，7.18(1H，m)，7.02(1H，dd)，5.70(1H，dd)，3.28(2H，m)，2.59(1H，m)，2.47(1H，m).
Embodiment 582-[[-3-amino-1-(3-pyridyl) propyl group] the oxygen base]-a) [3-oxo-3-(3-pyridyl) propyl group] carboxylamine 1 of 4-chloro-5-fluorine benzonitrile oxalate, 1-dimethyl ethyl ester
((2.24g 14.2mmol) in the solution in tetrahydrofuran (THF) (15ml), and stirred 1 hour at 20 ℃ 14.2mmol) to be added to the 3-bromopyridine for 7.1ml, 2M tetrahydrofuran solution with sec.-propyl bromination magnesium at 0 ℃.Add [3-(methoxymethyl amino)-3-oxopropyl carboxylamine 1,1-dimethyl ethyl ester (1.08g, the 4.65mmol) solution in tetrahydrofuran (THF) (6ml), and with this mixture stirring 18 hours.Handle this mixture with the saturated aqueous ammonium chloride quenching, with extracted with diethyl ether (3 times), with the organic extract liquid drying (using sodium sulfate) that merges, and evaporation, obtained oily matter.By the silicon-dioxide chromatogram purification, with gasoline-acetone wash-out, obtained 568mg (49%) book title compound, be colorless oil.MS APCI+ve m/ z 251[(M+H) +] .b) [3-hydroxyl-3-(3-pyridyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester
At 0 ℃, borine (3.0ml, 1M tetrahydrofuran solution) is added to (3 α S)-tetrahydrochysene-1-methyl-3,3-phenylbenzene-3H-pyrrolo-[1,2-c] [1,3,2] in the solution of oxa-azepine boron heterocyclic pentylene (0.22ml, 1M toluene solution) in tetrahydrofuran (THF) (5ml).(1.13g, the 4.52mmol) solution in tetrahydrofuran (THF) (3ml) stirred 24 hours at 20 ℃ then to add step (a) product with 30 minutes.Add methyl alcohol,, add methyl alcohol (15ml) and 2M hydrochloric acid (5ml), and stirred 45 minutes this solution evaporation.Add wet chemical and tert-Butyl dicarbonate (250mg), and extract this mixture with ethyl acetate (2 *) and methylene dichloride (4 *).With organic extract liquid drying (using sodium sulfate), evaporation, and, use the methylene chloride-methanol wash-out by the silica gel chromatography purifying, and obtained 928mg (73%) book title compound, be colorless oil.MS APCI+ve m/ z 253[(M+H) +] .c) [(3-(5-chloro-2-cyano group-4-fluorophenoxy)-3-(3-pyridyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester
Sodium hydride (141mg, 60% oil suspension) is added to step (b) product, and (785mg, 2.96mmol) and 4-chloro-2, (546mg is 3.75mmol) in the solution tetrahydrofuran (THF) (9ml) in, and with gained suspension stirring 0.5 hour for 5-difluoro benzonitrile.Handle this mixture with the saturated aqueous ammonium chloride quenching, alkalize to pH8, and with ethyl acetate extraction (3 times).With the organic extract liquid drying (using sodium sulfate) that merges, evaporation, and,, obtained 1.05g (88%) book title compound with gasoline-acetone wash-out by the silica gel chromatography purifying, be colorless oil.MS APCI+ve m/ z 406[(M+H) +] .d) 2-[[-3-amino-1-(3-pyridyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile oxalate
(227mg, 0.56mmol) solution stirring in 4M HCl De dioxane solution (4ml) is 0.5 hour with step (c) product.Add wet chemical, with this mixture of dichloromethane extraction, with organic extract liquid drying (using sodium sulfate), evaporation, and by the silica gel chromatography purifying, the methanol solution wash-out with methylene dichloride-3M ammonia has obtained light yellow gum (167mg).In the solution of this amine in Virahol (3ml), add the solution of oxalic acid (23mg) in hot methanol (0.3ml).Collect the formed crystal of cooling, drying has obtained this title compound of 180mg (100%), is white solid.MS?APCI+ve m/z306[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.66(d，1H)，8.56(dd，1H)，8.02(d，1H)，7.82(dt，1H)，7.52(d，1H)，7.46(dd，1H)，6.42(s，2H)，5.92(dd，1H)，2.89(t，2H)，2.37-2.27(m，1H)，2.21-2.10(m，1H).
Embodiment 594-chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridyl) propoxy-] a) [(3-(5-chloro-2-cyano group-4-fluorophenoxy)-3-(3-pyridyl) propyl group] carboxylamine 1 of benzonitrile oxalate, 1-dimethyl ethyl ester
With sodium hydride (34.2mg, 60% oil suspension, 0.86mmol) be added to embodiment 58 (c) product (219mg, 0.54mmol) and methyl-iodide (0.2ml 3.2mmol) in the solution in tetrahydrofuran (THF) (4ml), and stirred 3 hours.Add aqueous ammonium chloride solution, with this mixture of dichloromethane extraction (3 times).With the organic extract liquid drying (using sodium sulfate) that merges, evaporation, and,, obtained the book title compound with gasoline-acetone wash-out by the silica gel chromatography purifying, be colorless oil (157mg, 69%).MS APCI+ve m/ z 420[(M+H) +] .b) 4-chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridyl) propoxy-] the benzonitrile oxalate
This title compound is that the method by embodiment 58 (d) is made by embodiment 59 (a) product.MS?APCI+ve? m/z?320[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.67(d，1H)，8.57(d，1H)，8.03(d，1H)，7.83(d，1H)，7.54(d，1H)，7.47(dd，1H)，5.88(t，1H)，3.11-2.95(m，2H)，2.59(s，3H)，2.45-2.32(m，1H)，2.30-2.19(m，1H).
Embodiment 60 γ-[2-chloro-5-(trifluoromethyl) phenoxy group]-3-pyridine propanamine oxalate is [(3-(2-chloro-5-4-trifluoromethylphenopendant)-3-(3-pyridyl) propyl group]-carboxylamine 1 a), 1-dimethyl ethyl ester
At 0 ℃, with diethyl azodiformate (0.71ml, 4.47mmol) be added to [3-hydroxyl-3-(3-pyridyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester (embodiment 58 (b)) (291mg, 1.15mmol), 2-chloro-5-trifloro methyl phenol (232mg, 1.18mmol) and triphenylphosphine (455mg, 1.73mmol) in the solution in tetrahydrofuran (THF) (6ml), and 20 ℃ of stirrings 18 hours.Should react vacuum concentration,,, obtain book title compound (394mg, 79%) with gasoline-ether wash-out by the silicon-dioxide residue purified by chromatography.MS APCI+ve m/ z 431[(M+H) +] .b) γ-[2-chloro-5-(trifluoromethyl) phenoxy group]-3-pyridine propanamine oxalate
This title compound is that the method by embodiment 58 (d) makes with embodiment 60 (a) product.MS?APCI+ve? m/z?331[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)δ8.64(d，1H)，8.54(dd，1H)，7.99(s，2H)，7.81(dt，1H)，7.69(d，1H)，7.44(dd，1H)，7.36-7.28(m，2H)，5.93(dd，1H)，3.02-2.91(m，2H)，2.42-2.12(m，2H).
Embodiment 612-[3-amino-1-(6-methoxyl group-2-pyridyl) propoxy-]-a) [3-(6-methoxyl group-2-pyridyl)-3-oxopropyl] carboxylamine 1 of 4-chloro-5-fluorine benzonitrile oxalate, 1-dimethyl ethyl ester
At-78 ℃, (the 2.5M hexane solution, (690mg 4.0mmol) in the solution in tetrahydrofuran (THF) (4ml), and stirred 1 hour 1.4ml) to be added to 6-bromo-2-methoxypyridine with butyllithium.Add [3-(methoxymethyl amino)-3-oxopropyl] carboxylamine 1, and 1-dimethyl ethyl ester (344mg, the 1.42mmol) solution in tetrahydrofuran (THF) (3ml), and this mixture is warmed to 0 ℃ with 3 hours.Handle this mixture with the saturated aqueous ammonium chloride quenching, with ethyl acetate extraction (3 times).With the organic extract liquid drying (using sodium sulfate) that merges, evaporation, and,, obtained the book title compound with gasoline-acetone wash-out by the silicon-dioxide chromatogram purification, be colorless oil (291mg, 73%).MS APCI+ve m/ z281[(M+H) +] .b) [3-hydroxyl-3-(6-methoxyl group-2-pyridyl)-propyl group] carboxylamine 1,1-dimethyl ethyl ester
With embodiment 61 (a) product (489mg, 1.75mmol) and Sodium Borohydride (133mg, 3.52mmol) mixture in tetrahydrofuran (THF) (4ml) stirred 5 hours.Add 2M hydrochloric acid, with this mixture ethyl acetate extraction (3 times).With the organic extract liquid drying (using sodium sulfate) that merges, evaporation, and,, obtained the book title compound with gasoline-ether wash-out by the silicon-dioxide chromatogram purification, be colorless oil (446mg, 90%).MS APCI+ve m/ z 283[(M+H) +] .c) [(3-(5-chloro-2-cyano group-4-fluorophenoxy)-3-(6-methoxyl group-2-pyridyl)-propyl group]-carboxylamine 1,1-dimethyl ethyl ester
The book title compound is the method by embodiment 58 (c), uses [3-hydroxyl-3-(6-methoxyl group-2-pyridyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester (embodiment 61 (b)) and 4-chloro-2, and 5-difluoro benzonitrile makes.MS APCI+ve m/ z 436[(M+H) +] .d) 2-[3-amino-1-(6-methoxyl group-2-pyridyl) propoxy-]-4-chloro-5-fluorobenzamide oxalate
This title compound is that the method by embodiment 58 (d) is made by embodiment 61 (c) product.MS?APCI+ve? m/z?336[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.05(d，1H)，7.76(t，1H)，7.48(d，1H)，7.04(d，1H)，6.80(d，1H)，5.71(t，1H)，3.85(s，3H)，3.04-2.95(m，2H)，2.39-2.25(m，2H).
Embodiment 622-[[(1R)-and 3-amino-1-(5-methyl-3-isoxazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile fumarate
By the method for describing in embodiment 89 steps (a)-(c) and embodiment 93 steps (a)-(c), 5-methyl-isoxazole-3-formic acid is transformed the cost title compound, obtained solid.MS?APCI+ve? m/z?310[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.04(1H，d)，7.58(1H，d)，6.40(2H，s)，6.34(1H，s)，5.99-5.91(1H，m)，2.94(2H，t)，2.40(3H，s)，2.38-2.29(1H，m)，2.26-2.15(1H，m).
Embodiment 632-[3-amino-1-(1,6-dihydro-6-oxo-2-pyridyl) propoxy-]-4-chloro-5-fluorine benzonitrile oxalate
(313mg, 0.932mmol) solution in 62% aqueous solution of hydrogen bromide (2ml) was in 70 ℃ of heating 5.5 hours with embodiment 61 (d) product.Add wet chemical, and with this mixture of dichloromethane extraction.With organic extract liquid drying (using sodium sulfate), evaporation, and by the silicon-dioxide chromatogram purification, methanol solution wash-out with methylene dichloride-7M ammonia, use methanol-eluted fractions then, obtained successively: 2-[3-amino-1-(6-methoxyl group-2-pyridyl) propoxy-]-4-chloro-5-fluorobenzamide, 33.8mg.Oxalate is that the method by embodiment 58 (d) makes, and is solid (31.7mg).MS APCI+ve m/ z 354[(M+H) +]. 1H NMR 400MHz (d 6-DMSO) 8.11-7.88 (m, 4H), 7.73 (ddd, 1H), 7.65 (d, 1H), 7.38 (d, 1H), 7.07 (d, 1H), 6.78 (d, 1H), 5.76-5.70 (m, 1H), 3.85 (s, 3H), 3.04-2.89 (m, 2H), 2.38-2.20 (m, 2H); 2-[3-amino-1-(1,6-dihydro-6-oxo-2-pyridyl) propoxy-]-4-chloro-5-fluorine benzonitrile, 9.5mg converts it into oxalate according to the method for embodiment 58 (d), has obtained solid (5.3mg).MS?APCI+ve? m/z?322[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.08(d，1H)，7.99-7.76(m，2H)，7.53(t，1H)，7.34(d，1H)，6.45(d，2H)，5.48(s，1H)，2.94(s，2H)，2.39-2.17(m，2H).
Embodiment 64 (R)-γ-[2-chloro-5-(trifluoromethyl) phenoxy group]-2-pyridine propylamine dihydrochloride is [3-oxo-3-(2-pyridyl) propyl group] carboxylamine 1 a), 1-dimethyl ethyl ester
Under nitrogen atmosphere, 2-bromopyridine (3.16g) is cooled to-60 ℃ in anhydrous diethyl ether (50ml).The dropping n-Butyl Lithium (the 2.5M hexane solution, 8.5ml), and-60 ℃ of continuation stirrings 15 minutes.Drip (methoxymethyl amino)-3-oxopropyl] carboxylamine 1, the solution of 1-dimethyl ethyl ester (2.32g) in ether (20ml) is reflected at this-40 ℃ and stirred 1 hour, stirs 0.5 hour at 0 ℃ then.Handle this reaction with the saturated aqueous ammonium chloride quenching, and use ethyl acetate extraction.With organic extract liquid water successively, salt water washing, use dried over mgso, be evaporated to oily matter, it is crossed silicagel column, use hexane: ethyl acetate (4: 1) wash-out, obtained product, be light yellow oil (1.4g).MS APCI+ve m/ z 251[(M+H) +]. 1H NMR 300MHz (CDCl 3) 8.68 (1H, dt), 8.03 (1H, d), 7.84 (1H, td), 7.48 (1H, ddd), 5.10 (1H, s), 3.56 (2H, q), 3.43 (2H, t), 1.43 (9H, s) .b) [(3S)-and 3-hydroxyl-3-(2-pyridyl) propyl group] carboxylamine, 1,1-dimethyl ethyl ester
Method by embodiment 68 (a) is reduced step (a) product (0.6g), has obtained clarifying oily matter (0.24g). 1H NMR 400MHz (CDCl 3) 8.53 (1H, d), 7.70 (1H, dd), 7.36 (1H, d), 7.20 (1H, dd), 5.04 (1H, s), 4.82 (1H, dt), 4.65 (1H, s), 3.45 (1H, m), 3.33-3.17 (1H, m), 2.09 (1H, dd), 1.84-1.71 (1H, m), 1.44 (9H, s) .c) (R)-3-[2-chloro-5-(trifluoromethyl) phenoxy group]-3-(2-pyridyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester
Method with step (b) product (0.24g) and 2-chloro-4-trifloro methyl phenol carry out description among the embodiment 8 (a) has obtained product, is oily matter (0.3g).MS APCI+ve m/ z 431[(M+H) +]. 1H NMR 400MHz (CDCl 3) 8.60 (1H, dd), 7.67 (1H, td), 7.47 (1H, d), 7.37 (1H, d), 7.22 (1H, ddd), 7.11 (1H, dd), 6.95 (1H, d), 5.44 (1H, dd), 5.15 (1H, s), 3.45 (1H, dq), 3.30 (1H, dt), 2.38-2.20 (2H, m), 1.40 (9H, s) .d) (R)-γ-[2-chloro-5-(trifluoromethyl) phenoxy group]-2-pyridine propylamine dihydrochloride
Method with step (c) product (0.3g) carries out description among the embodiment 88 (b) has obtained product, is white solid (0.25g).MS?APCI+ve? m/z?331[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.63(1H，dd)，8.11(3H，s)，7.88(1H，td)，7.71(1H，d)，7.47(1H，d)，7.40(1H，ddd)，7.30(1H，d)，7.24(1H，d)，5.84(1H，dd)，3.01(2H，d)，2.43-2.23(2H，m).
Embodiment 652-[3-amino-1-(6-bromo-3-pyridyl) propoxy-]-a) [3-(6-bromo-3-pyridyl)-3-oxopropyl] carboxylamine 1 of 4-benzyl chloride nitrile oxalate, 1-dimethyl ethyl ester
The book title compound be method by embodiment 58 (a) by 2,5-dibromo pyridine and [3-(methoxymethyl amino)-3-oxopropyl] carboxylamine 1,1-dimethyl ethyl ester makes. 1H NMR 300MHz (CDCl 3) 8.90 (1H, d), 8.07 (1H, dd), 7.62 (1H, dd), 5.07 (1H, s), 3.53 (1H, q), 3.50 (1H, q), 3.19 (2H, t), 1.43 (9H, s) .b) [3-(6-bromo-3-pyridyl)-3-hydroxypropyl] carboxylamine 1,1-dimethyl ethyl ester
(645mg, 1.96mmol) (115mg, 3.04mmol) mixture in tetrahydrofuran (THF) (5ml) stirred 18 hours with Sodium Borohydride with embodiment 65 (a) product.Add 2M hydrochloric acid, with this mixture of ethyl acetate extraction (3 times).With the organic extract liquid drying (using sal epsom) that merges, evaporation, and, use the ether wash-out by the silica gel chromatography purifying, and obtained the book title compound, be colorless oil (6.60g). 1H NMR 300MHz (CDCl 3) 8.33 (1H, d), 7.63 (1H, dd), 7.46 (1H, d), 4.95-4.86 (1H, m), 4.78-4.69 (1H, m), 4.33-4.27 (1H, m), 3.68-3.51 (1H, m), 3.22-3.09 (1H, m), and 1.89-1.66 (2H, m), (1.46 9H, s) .c) [3-(6-bromo-3-pyridyl)-3-(5-chloro-2-cyano-benzene oxygen) propyl group] carboxylamine 1,1-dimethyl ethyl ester
The book title compound is that the method by embodiment 60 (a) is made by embodiment 65 (b) product and 4-chloro-2-hydroxy benzonitrile. 1H NMR 300MHz (CDCl 3) 8.40 (1H, d), 7.65 (1H, dd), 7.55-7.41 (1H, m), 7.33 (1H, d), 7.06-6.93 (1H, m), 6.80 (1H, d), 5.38 (1H, dd), 4.84 (1H, s), 3.45-3.28 (2H, m), 2.36-2.03 (2H, m), 1.44 (9H, s) .d) 2-[3-amino-1-(6-bromo-3-pyridyl) propoxy-]-4-benzyl chloride nitrile oxalate
This title compound is that the method by embodiment 58 (d) is made by embodiment 65 (c) product.MS?APCI+ve? m/z?366[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.50(s，1H)，7.85-7.70(m，3H)，7.31(s，1H)，7.21(dd，1H)，5.96-5.88(m，1H)，2.94-2.86(m，2H)，2.39-2.07(m，2H).
Embodiment 662-[[3-amino-1-(5-isoxazolyl) propyl group] the oxygen base]-a) N-methoxyl group-N-methyl-5-Isoxazolecarboxamidederivatives of 4-benzyl chloride nitrile oxalate
Jiang isoxazole-5-formic acid (2.81g), N-methoxyl group-N-methylamine hydrochloride (2.49g), EDCI (4.96g), dimethyl aminopyridine (3.15g) and the solution stirring of 4-methylmorpholine (2.8ml) in methylene dichloride (20ml) 18 hours.Add 2M hydrochloric acid, with this mixture of dichloromethane extraction (3 times).Organic layer is used sodium bicarbonate aqueous solution and salt water washing successively, merge, dry (using sal epsom), evaporation, and,, obtained the book title compound with gasoline-ether wash-out by the silica gel chromatography purifying, be colorless oil (2.94g, 76%). 1H NMR 300MHz (CDCl 3) 8.35 (1H, d), 6.89 (1H, d), 3.83 (3H, s), 3.39 (3H, s) .b) 3-chloro-1-(5-isoxazolyl)-1-propantheline
At-78 ℃, vinyl bromination magnesium (20ml, 1M tetrahydrofuran solution) is added to embodiment 66 (a) product, and (2.59g 16.6mmol) in the solution in tetrahydrofuran (THF) (35ml), and was warmed to 0 ℃ with 2.5 hours.After being cooled to-50 ℃, this mixture is poured in the excessive ice-cold 2M hydrochloric acid lentamente.With this mixture of extracted with diethyl ether (5 times).With organic extract liquid drying (using sal epsom), and evaporation, brown oil obtained.Add the diethyl ether solution (20ml) of 1M hydrogenchloride, and stirred 40 minutes.Solvent removed in vacuo has obtained book title compound (2.0g, 75%). 1H NMR 300MHz (CDCl 3) 8.39 (1H, s), 6.96 (1H, s), 3.91 (2H, t), 3.49 (2H, t) .c) α-(2-chloroethyl)-5-isoxazole methyl alcohol
At 0 ℃, borine (4.2ml, 1M tetrahydrofuran solution) is added to (3 α S)-tetrahydrochysene-1-methyl-3,3-phenylbenzene-3H-pyrrolo-[1,2-c] [1,3,2] in the solution of oxa-azepine boron heterocyclic pentylene (0.06ml, 1M toluene solution) in tetrahydrofuran (THF) (5ml).(998mg, the 6.25mmol) solution in tetrahydrofuran (THF) (5ml) so stirred 4 hours at 20 ℃ to add embodiment 66 (b) product lentamente.Add methyl alcohol, with this solution evaporation, with resistates and methanol azeotropic.By the silicon-dioxide chromatogram purification, with gasoline-ether purifying, obtained the book title compound, be colorless oil (562mg, 56%).MS APCI+ve m/ z 162[(M+H) +] .d) 4-chloro-2-[3-chloro-1-(5-isoxazolyl) propoxy-]-benzonitrile
This compound is to use α-(2-chloroethyl)-5-isoxazole methyl alcohol and 4-chloro-2-hydroxy benzonitrile to make by the method for embodiment 8 (a). 1H NMR 300MHz (CDCl 3) 8.26 (1H, d), 7.52 (1H, dd), 7.09 (1H, dt), 7.02 (1H, s), 6.36 (1H, t), 5.82-5.74 (1H, m), and 3.95-3.84 (1H, m), 3.81-3.70 (1H, m), 2.75-2.61 (1H, m), 2.54-2.40 (1H, m) .e) 2-[[3-amino-1-(5-isoxazolyl) propyl group] the oxygen base]-4-benzyl chloride nitrile oxalate
With embodiment 66 (d) product (100mg, 0.34mmol) and sodiumazide (34mg, 0.52mmol) solution stirring in DMSO (0.8ml) is 3 days.Add triphenylphosphine (88mg, 0.34mmol), tetrahydrofuran (THF) (2ml) and water (0.5ml), and with this solution stirring 2 days.By the silicon-dioxide chromatogram purification, the methanol solution wash-out with methylene dichloride-7M ammonia has obtained light yellow gum (27mg).In the solution of this amine in Virahol (3ml), add the solution of oxalic acid (9mg) in methyl alcohol (0.3ml).Be collected in the crystal that cooling forms down, drying has obtained this title compound, is white solid (91mg, 97%).MS?APCI+ve? m/z?278[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.61(1H，d)，7.82(1H，d)，7.51(1H，d)，7.25(1H，dd)，6.68(1H，d)，6.15(1H，t)，5.46(3H，s)，2.88(2H，t)，2.42-2.21(2H，m).
Embodiment 674-chloro-2-[3-(2-hydroxyethyl) amino]-1-(5-isoxazolyl) propoxy-] a) 4-chloro-2-[3-iodo-1-(5-isoxazolyl) propoxy-of benzonitrile oxalate] benzonitrile
With embodiment 66 (d) muriate (106mg, 0.356mmol) and the solution of sodium iodide (1g) in acetone (10ml) stirred 2 days at 20 ℃, stirred 1 day at 55 ℃.Solvent removed in vacuo adds entry, with this mixture of dichloromethane extraction (3 times).With organic layer drying (using sodium sulfate), evaporation has obtained book title compound (159mg, 100%). 1H NMR 300MHz (CDCl 3) 8.26 (1H, d), 7.53 (1H, d), 7.08 (1H, dd), 7.03 (1H, s), 6.35 (1H, s), 5.66 (1H, dd), 3.53-3.30 (2H, m), 2.72-2.04 (2H, m) .b) 4-chloro-2-[3-[(2-hydroxyethyl) amino]-1-(5-isoxazolyl) propoxy-] the benzonitrile oxalate
With 4-chloro-2-[3-iodo-1-(5-isoxazolyl) propoxy-] and benzonitrile (159mg, 0.41mmol) and the solution stirring of thanomin (0.2ml) in tetrahydrofuran (THF) (2ml) 2 days.Add entry, with this mixture of dichloromethane extraction.With the organic extract liquid drying (using sodium sulfate) that merges, evaporation, and by the silicon-dioxide chromatogram purification, the methanol solution wash-out with methylene dichloride-7M ammonia has obtained orange gum (40mg).Method according to embodiment 58 (d) prepares oxalate, has obtained this title compound, is white solid (40mg, 30%).MS?APCI+ve? m/z?322[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.63(d，1H)，7.83(d，1H)，7.52(d，1H)，7.27(dd，1H)，6.69(d，1H)，6.17(t，1H)，3.94(s，2H)，3.65(t，4H)，3.10(t，1H)，3.04(t，1H)，2.48-2.43(m，2H).
Embodiment 68 (R)-γ-(2, the 5-dichlorophenoxy)-5-isoxazole propanamine oxalate is (S)-α-(2-chloroethyl)-5-isoxazole methyl alcohol a)
At-10 ℃, borine (18ml, 1M tetrahydrofuran solution) is added to (3 α R)-tetrahydrochysene-1-methyl-3,3-phenylbenzene-3H-pyrrolo-[1,2-c] [1,3,2] in the solution of oxa-azepine boron heterocyclic pentylene (1.3ml, 1M toluene solution) in tetrahydrofuran (THF) (10ml).(6g, the 37.6mmol) solution in tetrahydrofuran (THF) (12ml) stirred 18 hours at-10 ℃ to 20 ℃ then to add 3-chloro-1-(3-isoxazolyl)-1-propantheline (embodiment 66 (b)) lentamente.Add methyl alcohol, with this solution evaporation, with resistates and methanol azeotropic.By the silicon-dioxide chromatogram purification, with gasoline-ether wash-out, obtained the book title compound, be colorless oil (774mg, 13%).MS APCI+ve m/ z 162[(M+H) +] .b) (S)-α-(2-azido-ethyl)-5-isoxazole methyl alcohol
With embodiment 68 (a) product (767mg, 4.76mmol) and sodiumazide (342mg, 5.26mmol) solution in DMSO (8ml) 65 ℃ the heating 18 hours.Add entry, and with this mixture of ethyl acetate extraction (3 times).With the organic extract liquid drying (using sal epsom) that merges, evaporation, and,, obtained the book title compound with gasoline-ether wash-out by the silicon-dioxide chromatogram purification, be colorless oil (454mg, 57%). 1H NMR 300MHz (CDCl 3) 8.22 (and 1H, d), 6.26 (1H, t), 5.12-5.03 (1H, m), 3.65-3.46 (2H, m), 2.54 (1H, d), 2.18-2.05 (2H, m) .c) (R)-γ-(2, the 5-dichlorophenoxy)-5-isoxazole propanamine oxalate
At 0 ℃, (0.23ml, (355mg is 1.35mmol) in the solution in tetrahydrofuran (THF) (3ml) 1.46mmol) to be added to triphenylphosphine with diethyl azodiformate.After 10 minutes, adding embodiment 68 (b) product (151mg, 0.90mmol) with 2, the 5-chlorophenesic acid (164mg, the 1.0mmol) solution in tetrahydrofuran (THF) (3ml), and 20 ℃ of stirrings 3 hours.(268mg 1.02mmol) and water (1ml), and stirred 2.5 days to add triphenylphosphine.Should react vacuum concentration, by the silicon-dioxide residue purified by chromatography, the methanol solution wash-out with methylene dichloride-7M ammonia has obtained light yellow gum (91mg).In the solution of this amine in Virahol (3ml), add the solution of oxalic acid (26mg) in methyl alcohol (1ml).Be collected in the crystal that cooling forms down, drying has obtained this title compound, is white solid (37mg, 14%).MS?APCI+ve? m/z?287[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.61(1H，d)，7.50(1H，d)，7.34(1H，d)，7.11(1H，d?of?d)，6.62(1H，d)，6.02(1H，d?of?d)，2.98(2H，t)，2.44-2.24(2H，m).
Embodiment 69 (R)-γ-(2, the 5-dichlorophenoxy)-N-methyl-amphetamine fumarate
According to the method for in embodiment 2 (b), describing, use [(3S)-and 3-hydroxyl-3-phenyl propyl] methyl carbamic acid 1,1-dimethyl ethyl ester (266mg, 1.0mmol) and 2, (163mg 1.0mmol) has made this title compound to the 5-chlorophenesic acid, converts it into fumarate at last.MS?APCI+ve? m/z?310[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.45-7.28(6H，m)，7.08(1H，d)，6.98-6.95(1H，dd)，6.45(2H，s)，5.75-5.71(1H，m)，2.95-2.90(2H，t)，2.50(3H，s)，2.34-2.08(2H，m).
Embodiment 70 (R)-γ-[2-chloro-5-(trifluoromethyl) phenoxy group]-N-methyl-amphetamine fumarate
According to the method for describing among the embodiment 2 (b), use [(3S)-and 3-hydroxyl-3-phenyl propyl] methyl carbamic acid 1,1-dimethyl ethyl ester (281mg, 1.06mmol) and 4-chloro-3-hydroxybenzotrifluoride (208mg, 1.06mmol), make this title compound, converted it into fumarate at last.MS?APCI+ve? m/z?344[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.67-7.64(1H，dd)，7.44-7.23(7H，m)，6.44(2H，s)，5.86-5.82(1H，m)，2.94(2H，t)，2.50(3H，s)，2.38-2.12(2H，m).
Embodiment 714-chloro-2-[[(1R)-and 3-(methylamino)-1-(2-thienyl) propyl group] the oxygen base] a) 4-chloro-2-[[(1R of benzonitrile oxalate)-3-chloro-1-(2-thienyl) propyl group] the oxygen base] benzonitrile
According to the method for describing among the embodiment 5 (a), use 4-chloro-2-hydroxy benzonitrile (303mg, 1.97mmol) and (S)-(349mg 1.97mmol), has made this title compound to α-(2-chloroethyl) thiophen(e)alcohol, is white crystalline solid (373mg, 61%). 1H NMR 300MHz (CDCl 3) 7.48-7.45 (1H, d), 7.33-7.31 (1H, dd), and 7.14-7.13 (1H, m), 7.03-6.97 (3H, m), 5.82-5.77 (1H, q), and 3.91-3.83 (1H, m), 3.67-3.59 (1H, m), 2.70-2.63 (1H, m), 2.42-2.33 (1H, m) .b) 4-chloro-2-[[(1R)-and 3-iodo-1-(2-thienyl) propyl group] the oxygen base] benzonitrile
(368mg 1.18mmol) transforms the cost title compound, has obtained light brown oily thing (408mg, 86%) with step (a) product according to the method for describing among the embodiment 5 (b).This product is directly used in next step.C) 4-chloro-2-[[(1R)-and 3-(methylamino)-1-(2-thienyl) propyl group] the oxygen base] the benzonitrile oxalate
According to the method for describing among the embodiment 5 (c), (400mg 0.99mmol) prepares this title compound, but will make oxalate (135mg, 34%) to use step (b) product.MS?APCI+ve m/z?307[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.79-7.77(1H，d)，7.58-7.56(1H，d)，7.47-7.46(1H，d)，7.27-7.26(1H，m)，7.20-7.18(1H，dd)，7.05-7.03(1H，m)，6.17-6.14(1H，t)，3.09-2.94(2H，m)，2.59(3H，s)，2.50-2.39(1H，m)，2.33-2.22(1H，m).
Embodiment 722-[[(1R)-and 3-amino-1-(3-furyl) propyl group] the oxygen base]-a) [3-(3-furyl)-3-oxopropyl]-carboxylamine 1 of 4-chloro-5-fluorine benzonitrile fumarate, 1-dimethyl ethyl ester
(5.88g 40mmol) is dissolved in the anhydrous tetrahydro furan (60ml), and this solution is cooled to-78 ℃ with 3-bromine furans.Drip n-Butyl Lithium (2.29M, 17.5ml, 40mmol), and with this solution-78 ℃ of stirrings.With 1 hour dropping [3-(methoxymethyl amino)-3-oxopropyl] carboxylamine 1, the solution of 1-dimethyl ethyl ester in tetrahydrofuran (THF) (40ml).This solution stirring is spent the night, be warmed to room temperature simultaneously.Add saturated aqueous ammonium chloride (30ml), and with this mixture (3 * 70ml) of ethyl acetate extraction.The organic extract liquid that merges is washed with water (3 * 30ml), dry (using sodium sulfate) and vacuum-evaporation.By quick silicon-dioxide residue purified by chromatography, use hexane: ethyl acetate (7: 3) wash-out, obtained this title compound, be light yellow solid (3.03g, 63%). 1H NMR 300MHz CDCl 38.05 (1H, d), 7.40-7.50 (1H, m), 6.72-6.82 (1H, m), 5.07 (1H, s), 3.41-3.60 (2H, m), 2.90-3.09 (2H, m), 1.43 (9H, s) .b) [(3R)-and 3-(3-furyl)-3-hydroxypropyl] carboxylamine 1,1-dimethyl ethyl ester
(1M toluene solution, 0.84ml 0.836mmol) are added in the anhydrous tetrahydro furan (50ml), and this solution is cooled to 0 ℃ with (S)-2-methyl-CBS-oxa-azepine boron heterocyclic pentene.Drip borine then: (1M, 5.02ml 5.02mmol), remain on temperature 0 ℃ to tetrahydrofuran complex simultaneously.This mixture was stirred 15 minutes, and (2.0g, the 8.36mmol) solution in tetrahydrofuran (THF) (50ml) remains on temperature 0 ℃ simultaneously to drip step (a) product with 1 hour then.Stirring is spent the night, and is warmed to room temperature simultaneously.Handle this reaction with methyl alcohol (5ml) quenching, and stir half an hour.Solvent removed in vacuo adds the methyl alcohol (20ml) of another aliquots containig.Solvent removed in vacuo, by quick silicon-dioxide residue purified by chromatography, use hexane: ethyl acetate (1: 1) wash-out, obtained this title compound, be colorless oil (1.685g, 84%). 1H NMR 300MHz (CDCl 3) 7.35-7.43 (2H, m), 6.40 (1H, t), 4.85 (1H, s), 4.69-4.77 (1H, m), 3.41-3.60 (1H, m), and 3.09-3.30 (2H, m), 1.80-1.92 (2H, m), 1.51 (9H, s) .c) [(3R)-3-(5-chloro-2-cyano group-4-fluorophenoxy)-3-(3-furyl) propyl group]-carboxylamine 1,1-dimethyl ethyl ester
With step (b) product (277mg, 1.15mmol) and 4-chloro-2,5-difluoro benzonitrile (199mg 1.15mmol) is dissolved in the dimethyl formamide (10ml), disposable adding sodium hydride (60%, 48mg, 1.2mmol).This is reflected at stirring at room 2 hours, uses saturated aqueous ammonium chloride (30ml) quenching to handle then, and with ethyl acetate extraction (3 * 60ml).The organic extract liquid that merges is washed with water (3 * 20ml), dry (using sodium sulfate) and vacuum-evaporation.By quick silicon-dioxide residue purified by chromatography, use hexane: ethyl acetate (3: 1) wash-out, obtained this title compound, be white crystalline solid (330mg, 73%). 1H NMR 300MHz (CDCl 3) 7.39-7.51 (2H, m), 7.36 (1H, s), 7.05 (1H, d), 6.43 (1H, t), 5.27-5.36 (1H, m), 5.19 (1H, s), and 3.18-3.43 (2H, m), 2.20-2.33 (1H, m), 2.02-2.13 (1H, m), 1.49 (9H, s) .d) 2-[[(1R)-and 3-amino-1-(3-furyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile fumarate
(150mg 0.3mmol) is dissolved in the 4M HCl De dioxane solution (10ml), and stirring at room 10 minutes with step (c) product.This reaction is placed ice bath, add saturated sodium bicarbonate aqueous solution (30ml) carefully.With this mixture of ethyl acetate extraction (3 * 50ml), with extraction liquid water (20ml) washing that merges, dry (using sodium sulfate) and vacuum-evaporation.By quick silicon-dioxide residue purified by chromatography, with the mixture wash-out of methanol solution in methylene dichloride of 5% 7N ammonia.Product is dissolved in the methyl alcohol (5ml), handles with the fumaric acid of monovalent.Stirred 10 minutes, solvent removed in vacuo is developed solid residue with amount of ethyl acetate then.Filter out white solid, and dry, obtained this title compound (50mg, 40%).MS?APCI+ve? m/z?295/297[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.05(1H，d)，7.87(1H，s)，7.75(1H，d)，7.65(1H，d)，6.65(1H，s)，6.51(2H，s)，5.77-5.89(1H，m)，2.95(2H，t)，2.10-2.44(2H，m).
Embodiment 734-chloro-5-fluoro-2-[[(1R)-and 1-(3-furyl)-3-methylamino) propyl group] the oxygen base]-a) [(3R)-3-(5-chloro-2-cyano group-4-fluorophenoxy)-3-(3-furyl) propyl group] carboxylamine 1 of benzonitrile fumarate, 1-dimethyl ethyl ester
With embodiment 72 (c) product (460mg 1.17mmol) is dissolved in the anhydrous tetrahydro furan (10ml), disposable adding sodium hydride (60%, 104mg, 2.6mmol).Should react and stir 10 minutes, (0.66ml 10.53mmol), and was reflected at stirring at room 24 hours with this to add methyl-iodide then.Handle this reaction with saturated aqueous ammonium chloride (30ml) quenching, with this mixture (3 * 70ml) of ethyl acetate extraction.The extraction liquid that merges is washed with water (3 * 30ml), dry (using sodium sulfate) and vacuum-evaporation have obtained this title compound (360mg, 75%). 1H NMR 300MHz (CDCl 3) 7.42 (2H, d), 7.26-7.36 (1H, m), 6.99 (1H, d), 6.42 (1H, s), 5.16-5.26 (1H, m), 3.27-3.56 (2H, m), 2.87 (3H, s), 2.21-2.43 (1H, m), 2.02-2.20 (1H, m), 1.40 (9H, s) .b) 4-chloro-5-fluoro-2-[[(1R)-and 1-(3-furyl)-3-methylamino) propyl group] the oxygen base]-the benzonitrile fumarate
(355mg 0.87mmol) with the middle method of describing of embodiment 72 (d), has made this title compound, is white solid (210mg, 78%) to use step (a) product.MS APCI+ve m/ z 309/311[(M+H) +]. 1H NMR 300MHz (d 6-DMSO) 7.98 (1H, d), 7.80 (1H, s), 7.68 (1H, t), 7.61 (1H, d), 6.53 (1H, t), 6.44 (2H, s), 5.76 (1H, t), 2.90 (2H, t), 2.57 (3H, s), 2.33 (1H, quintets), 2.17 (1H, m).
Embodiment 744-chloro-5-fluoro-2-[[(1R)-and 3-(methylamino)-1-(3-thienyl) propyl group] the oxygen base] a) N-methoxyl group-N-methyl-3-thenoyl amine of benzonitrile oxalate
With thenoic acid (10.04g, 78.3mmol) be dissolved in the methylene dichloride (250ml), and adding 4-dimethylaminopyridine (9.57g, 78.3mmol), N, O-dimethyl hydroxyl amine hydrochlorate (7.64g, 78.3mmol), N-methylmorpholine (8.6ml, 78.3mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (15.01g, 78.3mmol), and with gained solution stirring at room 24 hours.Should react dilution with methylene dichloride (100ml), use successively 2M hydrochloric acid (3 * 30ml), saturated sodium bicarbonate aqueous solution (2 * 30ml) and water (3 * 30ml) washing.With organic phase drying (using sal epsom), filter and evaporation, obtained this title compound, be colorless oil (12.3g, 92%). 1H NMR 300MHz (CDCl 3) 8.07 (1H, dd), 7.58 (1H, dd), 7.26-7.33 (1H, m), 3.66 (3H, s), 3.37 (3H, s) .b) 1-(3-thienyl)-2-propylene-1-ketone
(2.074g 12.1mmol) is dissolved in the anhydrous tetrahydro furan (30ml), and this solution is cooled to-10 ℃ with step (a) product.(1M, 14.5ml 14.5mmol), remain on temperature below 0 ℃ simultaneously to drip vinyl bromination magnesium.Gained solution was stirred 2.5 hours at 0 ℃, be warmed to room temperature then.This reaction mixture is poured in 2M hydrochloric acid (200ml) and the ice lentamente.(3 * 70ml), (2 * 30ml) and salt solution (20ml) washing, drying (using sal epsom) and vacuum-evaporation have obtained this title compound (1.288g, 77%) with the extraction liquid water that merges with ethyl acetate extraction. 1H NMR 300MHz (CDCl 3) 8.06-8.12 (1H, m), 7.58-7.64 (1H, m), 7.32-7.39 (1H, m), 6.99-7.12 (1H, m), 6.46 (1H, dd), 5.89 (1H, dd) .c) 3-chloro-1-(3-thienyl)-1-propantheline
(1.288g 9.3mmol) is dissolved in the mixture of ether (30ml) and methylene dichloride (20ml), adds the diethyl ether solution (25ml) of 1M hydrogenchloride with step (b) product.This was reflected at stirring at room 18 hours.Solvent removed in vacuo has obtained this title compound (1.482g, 91%). 1H NMR 300MHz (CDCl 3) 8.02-8.12 (and 1H, m), 7.51-7.61 (1H, m), 7.30-7.40 (1H, m), 3.90 (2H, t), 3.37 (2H, t) .d) (R)-α-(2-chloroethyl)-3-thiophen(e)alcohol
((984mg 5.6mmol), has made this title compound to 3-thienyl-1-propantheline, is colorless oil (647mg, 65%) to use middle method of describing of embodiment 72 (b) and 3-chloro-1-. 1H NMR 300MHz (CDCl 3) 7.29-7.36 (1H, m), 7.20-7.27 (1H, m), and 7.04-7.12 (1H, m), 5.02-5.09 (1H, m), 3.70-3.82 (1H, m), and 3.52-3.62 (1H, m), 2.08-2.34 (2H, m), 1.95 (1H, d) .e) 4-chloro-2-[[(1R)-and 3-chloro-1-(3-thienyl)-propyl group] the oxygen base]-5-fluoro-benzonitrile
(322mg, 1.84mmol), 4-chloro-2, (320mg 1.84mmol) and the method for describing among the embodiment 72 (c), has made this title compound (540mg, 89%) to 5-difluoro benzonitrile to use step (d) product. 1H NMR 300MHz (CDCl 3) 7.35-7.40 (1H, m), 7.29-7.34 (1H, m), 7.25-7.28 (1H, m), 7.11 (1H, dt), 6.95-6.99 (1H, m), 5.54-5.63 (1H, m), and 3.78-3.90 (1H, m), 3.55-3.66 (1H, m), 2.53-2.65 (1H, m), 2.21-2.35 (1H, m) .f) 4-chloro-5-fluoro-2-[[(1R)-and 3-iodo-1-(3-thienyl)-propyl group] the oxygen base] benzonitrile
Use method and the 4-chloro-2-[[(1R of embodiment 5 (b))-3-chloro-1-(3-thienyl) propyl group] the oxygen base]-(520mg 1.57mmol), has made this title compound (640mg, 97%) to 5-fluorine benzonitrile. 1H NMR 300MHz (CDCl 3) 7.35-7.39 (1H, m), 7.29-7.34 (2H, m), and 7.09-7.12 (1H, m), 6.95-6.99 (1H, m), 5.42-5.51 (1H, m), and 3.37-3.47 (1H, m), 3.16-3.26 (1H, m), 2.51-2.61 (1H, m), 2.26-2.38 (1H, m) .g) 4-chloro-5-fluoro-2-[[(1R)-and 3-(methylamino)-1-(3-thienyl) propyl group] the oxygen base] the benzonitrile oxalate
(210mg 0.5mmol) with the middle method of describing of embodiment 5 (c), replaces hydrochloric acid with oxalic acid, has made this title compound (148mg, 71%) to use step (f) product.MS?APCI+ve? m/z?325/327[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.01(1H，d)，7.58-7.64(2H，m)，7.51(1H，d)，7.12-7.16(1H，m)，5.80-5.90(1H，m)，2.90-3.08(2H，m)，2.63(3H，s)，2.30-2.43(1H，m)，2.13-2.28(1H，m).
Embodiment 754-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-1-(3-thienyl) propyl group] the oxygen base] the benzonitrile oxalate
With embodiment 74 (f) product (200mg 0.47mmol) is dissolved in the anhydrous tetrahydro furan (40ml), adds thanomin (5ml), and with this mixture stirring at room 3 days.Add entry (30ml), should reaction (3 * 60ml) with ethyl acetate extraction.The organic extract liquid that merges is washed with water (3 * 20ml), dry (using sal epsom) and vacuum-evaporation.By quick silicon-dioxide residue purified by chromatography, the mixture wash-out of methanol solution in methylene dichloride with 10% 7N ammonia is dissolved in product in the methyl alcohol, with the oxalic acid treatment of monovalent.This mixture was stirred 10 minutes, and solvent removed in vacuo is developed resistates with ethyl acetate then.Filter out white solid, drying has obtained this title compound.MS?APCI+ve? m/z?355/357[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.01(1H，d)，7.6](2H，t)，7.52(1H，d)，7.08-7.17(1H，m)，5.79-5.93(1H，m)，3.64(2H，t)，3.03(4H，dd)，2.32-2.47(1H，m)，2.18-2.32(1H，m).
Embodiment 762-[[(1R)-and the 3-[(2-amino-ethyl) amino]-1-(3-thienyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile oxalate
With embodiment 74 (f) product (200mg 0.47mmol) is dissolved in the anhydrous tetrahydro furan (40ml), adds quadrol (5ml), and with this mixture stirring at room 3 days.Add entry (30ml), should reaction (3 * 60ml) with ethyl acetate extraction.The organic extract liquid that merges is washed with water (3 * 20ml), dry (using sal epsom) and vacuum-evaporation.By quick silicon-dioxide residue purified by chromatography, the mixture wash-out of methanol solution in methylene dichloride with 10% 7N ammonia is dissolved in product in the methyl alcohol, and with the oxalic acid treatment of monovalent.This mixture was stirred 10 minutes, and solvent removed in vacuo is developed resistates in ethyl acetate.Filter out white solid, drying has obtained this title compound.MS?APCI+ve? m/z?354/356[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.00(1H，d)，7.56-7.68(2H，m)，7.52(1H，d)，7.15(1H，dd)，5.72-6.01(1H，m)，3.01-3.14(4H，m)，2.91-3.01(2H，m)，2.25-2.42(1H，m)，2.12-2.24(1H，m).
Embodiment 772-[[(1R)-and 3-amino-1-(3-thienyl) propyl group] the oxygen base]-a) 2-[[(1R of 4-chloro-5-fluorine benzonitrile oxalate)-3-azido--1-(3-thienyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile
With embodiment 74 (e) product (540mg 1.64mmol) is dissolved in the anhydrous dimethyl sulfoxide (20ml), add sodiumazide (170mg, 2.62mmol).This reaction is heated to 65 ℃, and stirred 12 hours, cooling, and add entry (60ml).(3 * 70ml), the extraction liquid of merging washes that (5 * 50ml), dry (using sal epsom) and vacuum-evaporation have obtained this title compound (535mg, 97%) with water with this mixture of ethyl acetate extraction. 1H NMR 300MHz (CDCl 3) 7.35-7.41 (1H, m), 7.27-7.34 (2H, m), and 7.07-7.11 (1H, m), 6.91-6.95 (1H, m), 5.38-5.47 (1H, m), and 3.58-3.70 (1H, m), 3.39-3.51 (1H, m), 2.28-2.45 (1H, m), 2.02-2.20 (1H, m) .b) 2-[[(1R)-and 3-amino-1-(3-thienyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile oxalate
With step (a) product (529mg 1.57mmol) is dissolved in the anhydrous tetrahydro furan (80ml), add triphenylphosphine (1.235g, 4.71mmol), and with this reaction mixture stirring at room 1 hour.Add entry (5ml), and should react and stir 64 hours.Add entry (100ml), should reaction (4 * 70ml) with ethyl acetate extraction.The organic extract liquid that merges is washed with water (3 * 25ml), dry (using sodium sulfate) and vacuum-evaporation.By quick silicon-dioxide residue purified by chromatography, the mixture wash-out of methanol solution in methylene dichloride with 5% 7N ammonia is dissolved in product in the methyl alcohol, with 1 normal oxalic acid treatment.This mixture was stirred 10 minutes, and solvent removed in vacuo is developed solid residue with ethyl acetate then.Filter out white solid and dry, obtained this title compound (380mg, 60%).MS?APCI+ve? m/z?311/313[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.01(1H，d)，7.55-7.67(2H，m)，7.47(1H，d)，7.13(1H，dd)，5.85(1H，dd)，2.81-2.99(2H，m)，2.25-2.39(1H，m)，2.09-2.23(1H，m).
Embodiment 784-chloro-2-[3-(methylamino)-1-(2-thiazolyl) propoxy-]-a) [3-hydroxyl-3-(2-thiazolyl) propyl group] methyl carbamic acid 1 of benzonitrile oxalate, 1-dimethyl ethyl ester
(482mg 2.94mmol) is dissolved in the anhydrous tetrahydro furan (15ml), and this solution is cooled to-78 ℃ with the 2-bromo thiazole.(2.4M, 1.25ml 3.0mmol), and are reflected at-70 ℃ with this and stir half an hour to drip n-Butyl Lithium.At-78 ℃ this drips of solution is added to methyl (3-oxopropyl)-carboxylamine 1 then, (600mg is 3.2mmol) in the solution in anhydrous tetrahydro furan (15ml) for 1-dimethyl ethyl ester.Add finish after, with this sluggish be warmed to ambient temperature overnight.Add saturated aqueous ammonium chloride (20ml), and should reaction (3 * 70ml) with ethyl acetate extraction.With extraction liquid water (20ml) washing that merges, dry (using sal epsom) and vacuum-evaporation.By quick silicon-dioxide residue purified by chromatography, use eluent ethyl acetate, obtained this title compound, be light orange oily matter (320mg, 40%). 1H NMR 300MHz (CDCl 3) 7.72 (1H, d), 7.28 (1H, d), 5.32-5.44 (1H, bs), 4.85-4.94 (1H, m), 3.88-4.01 (1H, m), 2.99-3.12 (1H, m), 2.90 (3H, s), 2.80-2.89 (1H, m), 2.26-2.41 (1H, m), 1.77-1.91 (1H, m), (1.50 9H, s) .b) [3-(5-chloro-2-cyano-benzene oxygen)-3-(2-thiazolyl) propyl group] methyl carbamic acid 1,1-dimethyl ethyl ester
With step (a) product (312mg, 1.15mmol), 2-hydroxyl-4-benzyl chloride nitrile (176mg, 1.15mmol) and triphenylphosphine (330mg 1.26mmol) is dissolved in the anhydrous tetrahydro furan (20ml), and this solution is cooled to 0 ℃.(219mg 1.26mmol), is warmed to room temperature lentamente with this solution, and stirs 18 hours to drip diethyl azodiformate.Solvent removed in vacuo, by quick silicon-dioxide chromatogram purification, use hexane: ethyl acetate (1: 1) wash-out has obtained this title compound (200mg, 43%). 1H NMR 300MHz (CDCl 3) 7.79 (1H, d), 7.34-7.53 (2H, m), 6.92-7.09 (2H, m), 5.61-5.71 (1H, m), 3.52-3.74 (1H, m), 3.31-3.45 (1H, m), 2.91 (3H, s), 2.82-2.92 (1H, m), 2.24-2.48 (1H, m), 1.40 (9H, s) .c) 4-chloro-2-[3-(methylamino)-1-(2-thiazolyl) propoxy-] the benzonitrile oxalate
(200mg 0.49mmol) is dissolved in the 4M hydrogenchloride De dioxane solution, and stirred 2.5 hours with step (b) product.Solvent removed in vacuo is applied to resistates on the acid SCX resin, with methyl alcohol (150ml) washing, and with methanol solution (50ml) releasing product of 7N ammonia.Solvent removed in vacuo is dissolved in resistates in the methyl alcohol (5ml), and with 1 normal oxalic acid treatment.Stirred 15 minutes, solvent removed in vacuo is developed resistates with amount of ethyl acetate then.Filter out white solid, and dry, obtained this title compound (17mg, 11%).MS?APCI+ve? m/z?308/310[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)7.79-7.93(3H，m)，7.51(1H，d)，7.26(1H，dd)，6.20-6.29(1H，m)，3.07(2H，t)，2.59(3H，s)，2.39-2.62(2H，m).
Embodiment 792-[[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base]-a) [3-oxo-3-[5-(trimethyl silyl)-2-thiazolyl] propyl group of 4-chloro-5-fluoro-benzonitrile hydrochloride] carboxylamine 1,1-dimethyl ethyl ester
(2.59g, 16.5mmol) and the method for describing among the embodiment 72 (a), changing part is to add to finish the back-70 ℃ of stirrings 2 hours, and-65 ℃ of stopped reactions, has made this title compound (1.48g, 55%) to use 2-(trimethyl silyl) thiazole. 1H NMR 300MHz (CDCl 3) 7.60 (1H, s), 4.76 (1H, s), 3.21 (2H, q), 2.91-3.08 (2H, m), 1.12 (9H, s), 0.01 (9H, s) .b) [[(3R)-and 3-hydroxyl-3-[5-(trimethyl silyl)-2-thiazolyl] propyl group] carboxylamine 1,1-dimethyl ethyl ester
(1.47g 4.47mmol) with the middle method of describing of embodiment 72 (b), has made this title compound (700mg, 47%) to use step (a) product. 1H NMR 300MHz (CDCl 3) 7.42 (1H, s), 4.68-4.79 (1H, m), 4.64 (1H, s), 4.28 (1H, s), 3.18-3.37 (1H, m), 2.79-2.95 (1H, m), 1.77-1.92 (1H, m), 1.51-1.65 (1H, m), 1.14 (9H, s), 0.03 (9H, s) .c) [(3R)-and 3-(5-chloro-2-cyano group-4-fluorophenoxy)-3-(2-thiazolyl) propyl group] carboxylamine, 1,1-dimethyl ethyl ester
Use the method for describing among step (b) product and the embodiment 72 (c) to make this title compound (376mg, 43%). 1H NMR 300MHz (CDCl 3) 7.79 (1H, d), 7.31-7.42 (2H, m), 7.14 (1H, d), 5.66 (1H, dd), 4.79 (1H, s), 3.44-3.60 (1H, m), and 3.22-3.33 (1H, m), 2.36-2.51 (1H, m), 2.20-2.34 (1H, m), 1.43 (9H, s) .d) 2-[[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile hydrochloride
(370mg 0.9mmol) is dissolved in the 4M hydrogenchloride De dioxane solution, and in stirring at room half an hour with step (c) product.Solvent removed in vacuo is with ethyl acetate and methanol mixture (14: 1) development resistates.Filter out white solid, drying has obtained this title compound (243mg, 70%).MS?APCI+ve? m/z?312/314[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.23(3H，br?s)，8.08(1H，d)，7.9(1H，d)，7.85(1H，d)，7.74(1H，d)，6.29(1H，dd)，2.90-3.07(2H，m)，2.35-2.48(2H，m).
Embodiment 80 γ-(2-chloro-5-nitro-phenoxy)-Corvitin hydrochloride is [3-(2-chloro-5-nitro-phenoxy)-3-phenyl propyl] methyl carbamic acid 1 a), 1-dimethyl ethyl ester
This compound is the method according to embodiment 2, uses α-[2-(methylamino) ethyl] phenylcarbinol and 2-chloro-5-nitrophenols to make.MS APCI+ve m/ z 321/323[(M-Boc+H) +] .b) γ-(2-chloro-5-nitro-phenoxy)-Corvitin hydrochloride
With [3-(2-chloro-5-nitro-phenoxy)-3-phenyl propyl] methyl carbamic acid, 1,1-dimethyl ethyl ester (132mg, 0.282mmol) in 4N HCl De dioxane solution (1ml), stirred 16 hours, filter out the gained solid, obtained product, be hydrochloride (60mg).MS?APCI+ve? m/z?321/323[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.89-8.73(2H，br?m)，7.83-7.73(3H，m)，7.47-7.39(4H，m)，7.36-7.30(1H，m)，5.92(1H，m)，3.11-3.00(2H，m)，2.58(3H，s)，2.42-2.31(1H，m)，2.28-2.18(1H，m).
Embodiment 81 (R)-γ-(5-chloro-2-nitro-phenoxy)-N-methylbenzene) a) [(3R)-3-(5-chloro-2-nitro-phenoxy)-3-phenyl propyl] methyl carbamic acid of propylamine fumarate, 1,1-dimethyl ethyl ester
This compound is the method by embodiment 20 (a), use [(3S)-and 3-hydroxyl-3-phenyl propyl] methyl carbamic acid 1,1-dimethyl ethyl ester and 5-chloro-2-nitrophenols make.APCI+ve m/ z 321/323[(M-BOC+H) +] .b) (R)-γ-(5-chloro-2-nitro-phenoxy)-N-methylbenzene) the propylamine fumarate
This compound is that the method by embodiment 20 (b) makes, and product is separated to as fumarate.MS?APCI+ve? m/z?321/323[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.92(1H，d)，7.45-7.39(4H，m)，7.36-7.31(1H，m)，7.27(1H，d)，7.14(1H，m)，6.46(2H，s)，5.88(1H，m)，2.96-2.86(2H，m)，2.50(3H，s)，2.29-2.19(1H，m)，2.17-2.09(1H，m).
Embodiment 824-chloro-5-fluoro-2-([(1R)-and the 3-[(2-fluoro ethyl) amino]-the 1-phenyl propyl] the oxygen base } the benzonitrile oxalate
This compound is the method by embodiment 43 (b), uses 2-fluoro ethyl amine and 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base }-5-fluorine benzonitrile makes.Free alkali is changed into oxalate.MS?APCI+ve? m/z?351[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)8.02(1H，d)，7.46-7.41(5H，m)，7.38-7.33(1H，m)，5.80-5.76(1H，m)，4.73(1H，t)，4.61(1H，t)，3.4-3.2(2H，m)，3.15-3.0(2H，m)，2.4-2.3(1H，m)，2.21-2.10(1H，m).
Embodiment 832-[[(1R)-and 3-amino-1-phenyl propyl] the oxygen base]-a) 4-bromo-2 of 4-bromo-5-fluorine benzonitrile oxalate, the 5-difluorobenzaldehyde
At-70 ℃, n-Butyl Lithium (1.95M hexane solution, 10.2ml)) is added drop-wise to 1,4-two bromo-2, (5g is 18.4mmol) in the stirred solution in ether (60ml) for 5-two fluorobenzene.After 1 hour, with 1 hour this solution is warmed to 0 ℃, dilute with water separates each layer, with sodium sulfate with the ether layer drying, and the evaporation.By column chromatography (Biotage) purifying,, obtained yellow oil (1.82g) with 5% ethyl acetate/hexane wash-out. 1H NMR 300MHz (CDCl 3) 10.28 (1H, s), 7.61 (1H, dd), 7.48 (1H, dd) .b) 4-bromo-2,5-difluoro benzonitrile
With 4-bromo-2, the 5-difluorobenzaldehyde (1.82g, 8.3mmol) and oxyamine-O-sulfuric acid (1.1 equivalents, 1.03g) in water (40ml) in 100 ℃ of heating 6 hours, cooling and is used ethyl acetate extraction.With organic layer drying (using sodium sulfate), and evaporation, obtained this title compound, be light yellow solid (1.2g). 1H NMR 300MHz (CDCl 3) 7.51 (1H, t), 7.39 (1H, t). (c) 4-bromo-2-[[(1R)-3-chloro-1-phenyl propyl] oxygen base 1-5-fluorine benzonitrile
This compound is the method by embodiment 43 (a), uses 4-bromo-2,5 difluoro benzonitriles and (R)-α-(2-chloroethyl) phenylcarbinol to make. 1H NMR 300MHz (CDCl 3) 8.02 (1H, s), 7.42-7.26 (5H, m), and 7.06-7.03 (1H, m), 5.46-5.43 (1H, m), 3.82-3.62 (1H, m), and 3.75-3.60 (1H, m), 2.75-2.5 (1H, m), 2.55-2.30 (1H, m) .d) 2-[[(1R)-and 3-azido--1-phenyl propyl] the oxygen base]-4-bromo-5-fluorine benzonitrile
This compound is the method by embodiment 68 (b), uses 4-bromo-2-[[(1R)-3-chloro-1-phenyl propyl] the oxygen base]-5-fluorine benzonitrile and sodiumazide make.MS APCI+ve m/ z 351[(M-N 2+ H) +] .e) 2-[[(1R)-3-amino-1-phenyl propyl] the oxygen base]-4-bromo-5-fluorine benzonitrile oxalate
This compound is the method by embodiment 77 (b), uses 2-[[(1R)-3-azido--1-phenyl propyl] the oxygen base]-4-bromo-5-fluorine benzonitrile makes.MS?APCI+ve? m/z?349/350[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)7.96(1H，d)，7.48-7.40(5H，m)，7.36-7.32(1H，m)，5.79-5.75(1H，dd)，2.95-2.82(2H，m)，2.32-2.20(1H，m)，2.10-2.03(1H，m).
Embodiment 843-[[(3R)-and 3-(2, the 5-dichlorophenoxy)-3-phenyl propyl] amino]-1-propylate hydrochlorate a) 1,4-two chloro-2-[[(1R)-3-chloro-1-phenyl propyl] the oxygen base] benzene
With 2,5-chlorophenesic acid (1.65g) is carried out the method for embodiment 5 (a), has obtained product, is clarifying oily matter (2.26g). 1H NMR 300MHz (CDCl 3) 7.39-7.36 (5H, m), 7.24 (1H, s), 6.82 (1H, dd), 6.74 (1H, d), 5.40 (1H, dd), 3.93-330 (1H, m), 3.69-3.57 (1H, m), 2.61-2.44 (1H, m), 2.33-2.18 (1H, m) .b) 1,4-two chloro-2-[[(1R)-3-iodo-1-phenyl propyl] the oxygen base] benzene
Carry out the method for embodiment 5 (b) with step (a) product (2.26g), obtained product, be yellow oil (2.78g). 1H NMR 300MHz (CDCl 3) 7.39-7.36 (5H, m), 7.25-7.23 (1H, m), 634-6.80 (1H, m), 6.76-6.73 (1H, m), and 5.32-5.25 (1H, m), 3.50-3.39 (1H, m), 3.33-3.24 (1H, m), and 2.60-2.49 (1H, m), (2.39-2.26 1H, m) .c) 3-[[(3R)-and 3-(2, the 5-dichlorophenoxy)-3-phenyl propyl] amino]-1-propylate hydrochlorate
Step (b) product (0.2g) and 3-amino-propanol (0.11g) are dissolved in the dimethyl formamide (4ml), and stirred 24 hours.This reaction is poured in the water, and be extracted in the ethyl acetate.With salt water washing organic extract liquid, to use dried over mgso, and be evaporated to driedly, the diethyl ether solution development with 1N HCl has obtained product, is white solid.MS?APCI+ve? m/z?354[(M+H) +]. 1H?NMR(d 6-DMSO)8.76(1H，s)，7.50-7.37(6H，m)，7.09(1H，d)，6.99(1H，dd)，5.77(1H，dd)，4.73(1H，s)，3.47(2H，t)，3.11-2.91(4H，m)，2.39-2.26(1H，m)，2.26-2.14(1H，m)，1.80-1.67(2H，m).
Embodiment 851-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-4-piperidine carbinols hydrochloride
Carry out the method for embodiment 84 (c) with embodiment 84 (b) product (0.2g) and 4-piperidine carbinols (0.11g), obtained product, be white solid.MS?APCI+ve? m/z?394[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)9.97(1H，s)，7.48-7.28(6H，m)，7.11(1H，d)，6.99(1H，dd)，5.77-5.67(1H，m)，4.68-4.59(1H，m)，3.56-3.44(2H，m)，3.28-3.20(2H，m)，3.19-3.07(2H，m)，2.99-2.83(2H，m)，1.86-1.74(2H，m)，1.68-1.53(1H，m)，1.51-1.35(2H，m)，2.44-2.24(2H，m).
Embodiment 86N-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-2-thiophene methyl amine hydrochloride
With embodiment 84 (b) (0.2g) and 2-thiophene methyl amine (0.06g) carry out the method for embodiment 84 (c), obtained product, be white solid.MS?APCI+ve? m/z?392[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)9.40-9.24(2H，m)，7.63(1H，dd)，7.49-7.36(5H，m)，7.36-7.28(2H，m)，7.12-7.05(2H，m)，7.03-6.95(1H，m)，5.83-5.74(1H，m)，4.46-4.37(2H，m)，3.16-2.97(2H，m)，2.40-2.29(1H，m)，2.28-2.18(1H，m).
Embodiment 87N-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-5-methyl-2-furylamine hydrochloride
Carry out the method for embodiment 84 (c) with embodiment 84 (b) product (0.2g) and 5-methyl-2-furylamine (0.06g), obtained product, be white solid.MS?APCI+ve? m/z?390[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)9.36-9.17(2H，m)，7.51-7.29(6H，m)，7.10-7.04(1H，m)，7.02-6.94(1H，m)，6.48(1H，d)，6.12(1H，dd)，5.82-5.71(1H，m)，4.20(2H，s)，3.12-2.94(2H，m)，2.39-2.13(2H，m)，2.26(3H，s).
Embodiment 884-chloro-2-[[(1R)-and 1-phenyl-3-(1-piperazinyl) propyl group] the oxygen base] a) 4-[(3R of benzonitrile dihydrochloride)-3-(5-chloro-2-cyano-benzene oxygen)-3-phenyl propyl]-1-piperazinecarboxylic acid 1,1-dimethyl ethyl ester
With 4-chloro-2-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base } benzonitrile (0.3g) and piperazinecarboxylic acid 1,1-dimethyl ethyl ester (0.4g) carries out embodiment 11 described methods, has obtained product, is clarifying gum (0.35g). 1H NMR 400MHz (CDCl 3) 7.45 (1H, d), 7.41-7.34 (5H, m), 6.92 (1H, dd), 6.86 (1H, d), 5.36 (1H, dd), and 3.49-3.34 (4H, m), 2.62-2.21 (7H, m), 2.11-1.96 (1H, m), 1.47 (9H, d) .b) 4-chloro-2-[[(1R)-and 1-phenyl-3-(1-piperazinyl) propyl group] the oxygen base]-the benzonitrile dihydrochloride
Step (a) product (0.35g) was stirred 3 hours in 4M HCl De dioxane solution (10ml), pour into then in the saturated sodium bicarbonate solution (100ml), and be extracted in the ethyl acetate.Extraction liquid is evaporated to dried, the diethyl ether solution development resistates with 1N HCl has obtained product, is white solid.MS?APCI+ve? m/z?356[(M+H) +]. 1H?NMR?400MHz(d 6-DMSO)9.81-9.42(2H，m)，7.78(1H，d)，7.53-7.25(6H，m)，7.15(1H，d)，5.99-5.84(1H，m)，3.94-3.03(12H，m).
Embodiment 895-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base]-a) N-methoxyl group-N-methyl-3-Isoxazolecarboxamidederivatives of 4-methyl benzonitrile fumarate
With 3-isoxazole carboxylic acid (4.2g), 4-dimethylaminopyridine (5.1g), N, O-dimethyl hydroxyl amine hydrochlorate (4.0g), N-methylmorpholine (4.2g) and 1-(3-diethylamino the propyl group)-mixture of 3-ethyl-carbodiimide hydrochloride (7.5g) in methylene dichloride (175ml) is in stirred overnight at room temperature.This reaction mixture is used 2N hydrochloric acid successively, and (dried over mgso is used in 100ml, saturated sodium bicarbonate (100ml), salt water washing, and evaporation, has obtained product, is dark orange (3.7g). 1H NMR 300MHz (CDCl 3) 8.48 (1H, d), 6.72 (1H, br s), 3.8 (3H, s), 3.4 (3H, s) .b) 1-(3-isoxazolyl)-2-propylene-1-ketone
Under nitrogen atmosphere, step (a) product (0.66g) is dissolved in the anhydrous tetrahydro furan (20ml), and is cooled to-30 ℃.(1M 6ml), is warmed to 0 ℃ with this reaction mixture, and stirs 2 hours under this temperature to drip the bromination vinyl magnesium with 5 minutes.This mixture is poured in the ice-cold 2N hydrochloric acid (50ml), and be extracted in the ethyl acetate.Water, salt water washing extraction liquid are used dried over mgso, and evaporation, have obtained dark-coloured oily matter (0.4g). 1H NMR 300MHz (CDCl 3) 8.53-8.48 (1H, m), 7.36-7.22 (1H, m), 6.88-6.81 (1H, m), 6.76-6.64 (1H, m), 6.07-6.00 (1H, m) .c) 3-chloro-1-(3-isoxazolyl)-1-propantheline
Step (b) product is handled with 1M HCl diethyl ether solution (5ml), stirring at room 4 hours.Removal of solvent under reduced pressure has obtained product then, is dark-coloured gum (0.42g). 1H NMR 300MHz (CDCl 3) 8.51 (and 1H, d), 6.79 (1H, d), 3.92 (2H, t), 3.57 (2H, t) .d) (S)-α-(2-chloroethyl)-3-isoxazole methyl alcohol
By the method for describing among the embodiment 68 (a) step (c) product (1g) is reduced, obtained product, be clarifying oily matter (0.5g). 1H NMR 300MHz (CDCl 3) 8.47-8.36 (1H, m), 6.43-6.38 (1H, m), 5.18 (1H, dt), and 3.87-3.75 (1H, m), 3.73-3.62 (1H, m), 2.71-2.61 (1H, m), 2.36-2.18 (2H, m) .e) 2-[[(1R)-3-chloro-1-(3-isoxazolyl) propyl group] the oxygen base]-5-fluoro-4-methyl-benzonitrile
According to the method for describing among the embodiment 5 (a), with step (d) product (0.47g) and the reaction of 5-fluoro-2-hydroxy-4-methyl benzonitrile, obtained product, be white solid (0.4g). 1H NMR 300MHz (CDCl 3) 8.42 (1H, t), 7.18 (1H, d), 6.94 (1H, d), 6.47 (1H, d), 5.78 (1H, dd), 3.97-3.82 (1H, m), and 3.80-3.67 (1H, m), 2.73-2.56 (1H, m), 2.43-2.29 (1H, m), 2.31 (3H, s) .f) 5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base]-4-methyl-benzonitrile fumarate
According to the method for embodiment 11, step (e) product (0.16g) and thanomin (0.3g) are reacted, obtained product, be white solid (0.14g).MS?APCI+ve? m/z?320[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.97(1H，s)，7.67(1H，d)，7.26(1H，d)，6.68(1H，s)，6.48(2H，s)，5.93(1H，s)，3.60(2H，s)，2.96(4H，d)，2.47-2.35(1H，m)，2.33-2.10(4H，m).
Embodiment 902-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-a) 2-[[(1R of 5-fluoro-4-methyl-benzonitrile fumarate)-3-azido--1-(3-isoxazolyl) propyl group] the oxygen base]-5-fluoro-4-methyl-benzonitrile
With embodiment 89 (e) product (0.2g) and sodiumazide (0.045g) in methyl-sulphoxide (5ml) in 60 ℃ of heating 24 hours, obtained product.MS APCI+ve m/ z 274[(M-28) +] .b) 2-[[(1R)-3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-5-fluoro-4-methyl-benzonitrile fumarate
Will be at the solution in the step (a) with tetrahydrofuran (THF) (10ml), water (1ml) and triphenylphosphine (0.3g) processing, and stirring at room 36 hours.This mixture is poured in the saturated sodium bicarbonate (20ml), and be extracted in the ethyl acetate.Extraction liquid is evaporated to dried, resistates is loaded on the ion exchange resin (SCX isolute), and with acetonitrile and methanol wash.Methanol solution with 7M ammonia elutes product from post, obtained oily matter, converts it into fumarate (0.104g).MS?APCI+ve? m/z?276[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.97(1H，d)，7.68(1H，d)，7.24(1H，d)，6.68(1H，d)，6.41(2H，s)，5.99-5.85(1H，m)，3.01-2.89(2H，m)，2.43-2.29(1H，m)，2.27-2.16(1H，m)，2.24(3H，s).
Embodiment 914-chloro-2-[[(1R)-and 3-[(1, the 1-dimethyl ethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base] a) (R)-α-(2-chloroethyl)-3-isoxazole methyl alcohol of benzonitrile fumarate
With embodiment 89 (c) product (3g) reduction, obtained product with the method for describing among the embodiment 66 (c), be clarifying oily matter (1.1g). 1H NMR 300MHz (CDCl 3) 8.40 (1H, d), 6.40 (1H, d), 5.25-5.13 (1H, m), 3.88-3.61 (2H, m), 2.42 (1H, d), 2.33-2.21 (2H, m) .b) 4-chloro-2-[[(1R)-3-chloro-1-(3-isoxazolyl) propyl group] the oxygen base] benzonitrile
Step (a) product (0.19g) and 2-fluoro-4-benzyl chloride nitrile (0.17g) are dissolved in the dimethyl formamide (5ml), and (60% oil suspension 0.06g) is handled with sodium hydride.After 2 hours, this reaction mixture is poured in the 2N hydrochloric acid (10ml), and be extracted in the ethyl acetate (50ml).Extraction liquid is used saturated sodium bicarbonate, salt water washing successively, use dried over mgso, and evaporation, yellow oil (0.29g) obtained.MS APCI+ve m/ z 298[(M+H) +]. 1H NMR 300MHz (CDCl 3) 8.44 (1H, d), 7.49 (1H, d), 7.13 (1H, d), 7.04 (1H, dd), 6.46 (1H, d), 5.82 (1H, dd), 3.88 (1H, ddd), 3.73 (1H, dt), and 2.73-2.57 (1H, m), (2.47-2.26 1H, m) .c) 4-chloro-2-[[(1R)-and 3-[1, the 1-dimethyl ethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base] the benzonitrile fumarate
With step (b) product (0.14g) and tert-butylamine (0.5g) reaction, obtained product according to the method for describing among the embodiment 12, be white solid (0.085g).MS?APCI+ve? m/z?334[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.96(1H，d)，7.77(1H，d)，7.40(1H，d)，7.20(1H，dd)，6.71(1H，t)，6.46(2H，s)，6.15-5.90(1H，m)，2.95(2H，t)，2.45-2.34(1H，m)，2.33-2.19(1H，m)，1.22(9H，s).
Embodiment 922-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-a) 2-[[(1R of 4-chloro-benzonitrile fumarate)-3-azido--1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-benzonitrile
Method with embodiment 91 (b) product carries out description among the embodiment 90 (a) has obtained product, then this product is directly carried out next step.B) 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-benzonitrile fumarate
Use step (a) product (0.14g) to carry out the method for describing among the embodiment 90 (b), obtained product, be white solid (0.05g).MS?APCI+ve? m/z?278[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.99(1H，d)，7.81(1H，d)，7.41(1H，d)，7.23(1H，dd)，6.72(1H，d)，6.41(2H，s)，6.08(1H，dd)，2.95(2H，t)，2.44-2.31(1H，m)，2.31-2.19(1H，m).
Embodiment 932-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-a) (R)-α-(2-azido-ethyl)-3-isoxazole methyl alcohol of 4-chloro-5-fluoro-benzonitrile
Embodiment 91 (a) product (0.17g) and sodiumazide (0.08g) were heated 4 hours in 70 ℃ in methyl-sulphoxide (3ml).Then this mixture is poured in the water, and used ethyl acetate extraction.Water, salt water washing extraction liquid are used dried over mgso, and evaporation has obtained product, is clarifying oily matter (0.15g).MS APCI+ve m/ z 141[(M-28) +]. 1H NMR 300MHz (CDCl 3) 8.47 (1H, d), 6.50 (1H, d), 5.18-4.98 (1H, m), 3.72-3.40 (2H, m), 2.70-2.47 (1H, m), 2.16-1.98 (2H, m) .b) 2-[[(1R)-3-azido--1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile
With step (a) product (0.1g) and 2, (60% oil suspension 0.035g) carries out the middle method of describing of embodiment 90 (a), has obtained product, is gum (0.15g) for 5-two fluoro-4-chloro-benzonitriles (0.18g) and sodium hydride.MS APCI+ve m/ z 294[(M-28) +] .c) 2-[[(1R)-3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile fumarate
Method with step (b) product (0.15g) and triphenylphosphine (0.3g) carry out description among the embodiment 90 (b) has obtained product, is solid (0.105g).MS?APCI+ve? m/z?296[(M+H) +]. 1H?NMR?300MHz(d 6-DMSO)8.99(1H，d)，8.04(1H，d)，7.61(1H，d)，6.74-6.68(1H，m)，6.40(2H，s)，6.09-6.00(1H，m)，3.00-2.89(2H，m)，2.43-2.32(1H，m)，2.29-2.18(1H，m).
Embodiment 94 (R)-γ-(2, the 5-dichlorophenoxy)-3-isoxazole propylamine fumarate is 3-[(1R a))-3-azido--1-(2, the 5-dichlorophenoxy) propyl group] isoxazole
Use the method for describing among the embodiment 93 (b), with embodiment 93 (a) product (0.17g) and 2,5-two chloro-fluorobenzene (0.4g) react, and have obtained product, are gum, use it for next step.B) (R)-γ-(2, the 5-dichlorophenoxy)-3-isoxazole propylamine fumarate
Method with step (a) product (0.1g) carries out description among the embodiment 90 (b) has obtained product, is solid (0.03g).MS?APCI+ve? m/z?287[(M+H) +]. 1H?NMR?300MHz(CD 3OD)8.72(1H，d)，7.39(1H，d)，7.13(1H，d)，7.02(1H，dd)，6.70(2H，s)，6.56(1H，d)，5.86-5.77(1H，m)，3.28-3.19(2H，m)，2.60-2.46(1H，m)，2.43-2.28(1H，m).
Screening
The pharmacologically active of test The compounds of this invention in following column filter.Screening 1
Can pass through based on people such as F rstermann, Eur.J.Pharm., 1992,225, the method for 161-165 comes the nitricoxide synthase of screening type (I) compound or its pharmacologically acceptable salt, enantiomorph or racemic modification to suppress active.Nitricoxide synthase will 3The H-L-arginine changes into 3The H-L-citrulline, this citrulline can separate by cation-exchange chromatography, and can come quantitative assay by liquid scintillation counting(LSC).
After inducing, be J774A-1 (deriving from the laboratory of Imperial CaneerResearch Fund) preparation enzyme by the mouse macrophage of cultivating.With the J774A-1 cell at additional 10% foetal calf serum, 4mM L-glutaminate and microbiotic (100 units/ml penicillin G, 100mg/ml Lian Meisu ﹠amp; 0.25mg/ml cultivate among the Dulbeccos Modified EaglesMedium (DMEM) amphotericin B).Allow cell contain the 35ml substratum and to contain 5% CO 2Moistening atmosphere in the 225cm of 37 ℃ of maintenances 3Carry out the routine growth in the flask.
Nitricoxide synthase is being produced when reacting Interferon, rabbit-g (IFNg) and lipopolysaccharides (LPS) by cell.From the flask of confluent culture, take out substratum, and replace with the 25ml that contains 1mg/ml LPS and 10 units/ml IFNg (each flask) fresh culture.Cultivate after 17-20 hour, in the cell sheet is swiped substratum from the flask surface, finish cell harvesting.By centrifugal (1000g, 10 minutes) collecting cell, and by preparing lysate in the solution that cell centrifugation group is added to the proteinase inhibitor mixture that contains 50mM Tris-HCl (pH7.5 is at 20 ℃), 10% (v/v) glycerine, 0.1% (v/v) Triton-X-100,0.1mM dithiothreitol (DTT) and comprise leupeptin (2mg/ml), Trypsin inhibitor SBTI (10mg/ml), Trypsin inhibitor,Trasylol (5mg/ml) and phenyl methyl sulfonic acid fluoride (50mg/ml).
In order to measure, with 25 μ l substrate mixture (50mM Tris-HCl (pH7.5,20 ℃), 400 μ M NADPH, 20 μ M flavin adenine dinucleotides, 20 μ M vitamin B2 phosphates, 4 μ M tetrahydrobiopterins, 12 μ M L-arginine and 0.025mCi L-[ 3H] arginine) be added in the hole of the 96 hole filter plates that contain the solution of 25 μ l test compounds in 50mM Tris-HCl (0.45 μ M aperture).Begin reaction by adding 50 μ l cellular lysate (preparing as mentioned above), after 1 hour, come termination reaction by adding the 50 μ l 3mM nitro arginine and the 21mM EDTA aqueous solution in incubated at room temperature.
Use Dowex AG-50W that the L-citrulline of mark and the L-arginine of mark are separated.With 150 μ l25% Dowex 50W (Na +Form) aqueous slurry is added to be measured in the mixture, then whole mixture is filled in the 96 hole flat boards.Take out 75 μ l filtrate samples, and be added in the 96 hole flat boards that contain the solid scintillator.After the sample drying, come quantitative assay L-citrulline by scintillation counting.
In typical experiment, the substrate activity is a 300dpm/75 μ l sample, increases to 1900dpm in the reagent contrast.Compound activity is with IC 50(in mensuration, enzyme being suppressed 50% drug concentrations) expression, IC 50(50% inhibition concentration) is that the aminoguanidine of 10 μ M is tested with this method of verification as standard.The compound of test certain limit concentration, and inhibition calculating IC from being obtained 50Value.At 100 μ M the compound of enzyme inhibition at least 25% being advised is active compound, and carries out at least repeated test again.Screening 2
Can confirm in following mensuration that compound also shows the activity of anti-people's inducible nitric oxide synthase.
With human colorectal cancer clone DLD-1 (derive from European Collection ofAnimal Cell Culture-clone number 90102540) in the RPMI1640 that is supplemented with 10% (v/v) foetal calf serum and 2mM L-glutaminate in 5% CO 2, grow under 37 ℃ of conditions.
Contain the people by adding and recombinate that (substratum of 1000 units/ml), TNF-α (200U/ml), IL-6 (200U/ml) and IL-1-β (250U/ml) is induced nitricoxide synthase to γ-IFN in cell.37 ℃ cultivate 18 hours after, take out substratum, and with warm phosphate buffered saline (PBS) washed cell.Having and do not having in the presence of the test compounds, with cell in the RPMI 1640 that contains 100 μ M L-arginine and 100 μ M verapamil-HCl in 37 ℃/5% CO 2Cultivated again under the condition 5 hours.
Measure nitrite and gather by isopyknic substratum and griess reagent (10mg/ml sulfanilamide (SN), 1mg N-(1-naphthyl) quadrol are in 1ml 2.5% (v/v) phosphoric acid) are mixed.With respect to the inhibition of calculating by the nitrite level of untreated cell generation in the presence of compound.Suppress the semilogarithmic plot of compound concentration is estimated IC from % 50Value.
When test, the compound of embodiment 1-94 shows the IC that is lower than 25 μ M at least one above-mentioned screening 50Value this means and estimates that they show useful therapeutic activity.

Claims (27)

1. formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification
Figure A0180548900021
Wherein: X and Y represent C1-4 alkyl, C1-4 alkoxyl group, halogen, CF independently 3, OCF 3, CN, C ≡ CH, S (O) mCH 3, S (O) pCF 3, NO 2Or NHCHO; M and p represent integer 0,1 or 2 independently; Z represents hydrogen or fluorine; V represents O; W represents phenyl or contains 1-3 the heteroatomic 5 or 6 yuan of fragrant heterocycles that are independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by one or more halogen, C1-4 alkyl, C1-4 alkoxyl group, OH, CN, NO of being independently selected from 2Or NR 4R 5Substituting group replace; Described alkyl or alkoxyl group can be chosen wantonly by one or more fluorine atoms and replace; R 1And R 2Represent H, C1-4 alkyl or C3-6 cycloalkyl independently; Described alkyl is optional to be replaced by following groups: C1-4 alkoxyl group, halogen, hydroxyl, NR 6R 7, phenyl or contain heteroatomic 5 or 6 yuan of aromatics or the saturated heterocyclic that 1-3 is independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by halogen, C1-4 alkyl, C1-4 alkoxyl group, CF 3, OCF 3, CN or NO 2Replace; Perhaps group NR 1R 2Representative is optional together also comprises one and is selected from O, S or NR 8The saturated nitrogen heterocyclic of other heteroatomic 4-8 unit; Described ring is optional to be replaced by C1-4 alkyl, C1-4 alkoxyl group or OH; Described alkyl is optional by C1-4 alkoxyl group, OH or NR 9R 10Replace; Perhaps group NR 1R 2The part of 5 yuan of aromatics nitrogen heterocyclics that also comprise an other N atom is chosen in representative wantonly together; R 4, R 5, R 6, R 7, R 9And R 10Represent H or C1-4 alkyl independently; R 8Represent H or C1-6 alkyl; Described alkyl is optional to be replaced by following groups: C1-4 alkoxyl group, OH, NR 11R 12, phenyl or contain heteroatomic 5 or 6 yuan of aromatics or the saturated heterocyclic that 1-3 is independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by halogen, C1-4 alkyl, C1-4 alkoxyl group, CF 3, OCF 3, CN or NO 2Replace; R 11And R 12Represent H or C1-4 alkyl independently; Be used for the treatment of or prevent to benefit from application in the medicine of disease that nitric oxide synthase activity suppresses or illness in preparation.
2. the application of claim 1 wherein mainly suppresses the inducible nitric oxide synthase.
3. be used for the treatment of or prevent application in the medicine of inflammatory diseases in preparation as the defined formula of claim 1 (I) compound or its pharmacologically acceptable salt, enantiomorph or racemic modification.
4. the application of claim 3, wherein said disease is an inflammatory bowel.
5. the application of claim 3, wherein said disease is a rheumatoid arthritis.
6. the application of claim 3, wherein said disease is an osteoarthritis.
As the defined formula of claim 1 (I) compound or its pharmacologically acceptable salt, enantiomorph or racemic modification preparation be used for the treatment of or the medicine of prevent irritation in application.
8. combine with cox 2 inhibitor as the defined formula of claim 1 (I) compound or its pharmacologically acceptable salt, enantiomorph or racemic modification and be used for the treatment of or prevent application in the medicine of inflammatory diseases in preparation.
9. treatment can be benefited from disease or illness that nitric oxide synthase activity suppresses or the method that reduces the danger of described disease or illness, comprise to suffer from or dangerous people's administering therapeutic significant quantity of suffering from described disease or illness as the defined formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification.
10. the methods of treatment of claim 9 wherein mainly suppresses the inducible nitric oxide synthase.
11. for to suffer from or the dangerous method of suffering from the human therapy inflammatory diseases of inflammatory diseases or reducing inflammatory diseases danger, described method comprise to described people's administering therapeutic significant quantity as the defined formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification.
12. the methods of treatment of claim 11, wherein said disease is an inflammatory bowel.
13. the method for claim 11, wherein said disease is a rheumatoid arthritis.
14. the methods of treatment of claim 11, wherein said disease is an osteoarthritis.
15. for to suffer from or the dangerous method of suffering from the human therapy pain of pain or reducing pain danger, described method comprise to described people's administering therapeutic significant quantity as the defined formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification.
16. for to suffer from or the dangerous method of suffering from the human therapy inflammatory diseases of inflammatory diseases or reducing inflammatory diseases danger, described method comprise to the co-administered treatment significant quantity of described people as the defined formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification and cox 2 inhibitor.
17. be used for the treatment of or prevent to benefit from the disease that nitric oxide synthase activity suppresses or the pharmaceutical preparation of illness, wherein comprise formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or the racemic modification for the treatment of significant quantity and with the pharmaceutically acceptable auxiliary agent of its blended, diluent or carrier.
18. be used for the treatment of or prevent to benefit from the pharmaceutical preparation that nitricoxide synthase is induced the disease or the illness of isoform activity inhibited, wherein comprise formula (I) compound or pharmaceutically acceptable salt thereof, enantiomorph or the racemic modification for the treatment of significant quantity and with the pharmaceutically acceptable auxiliary agent of its blended, diluent or carrier.
19. be used for the treatment of or prevent the pharmaceutical preparation of the claim 17 of inflammatory diseases.
20. formula (Ia) compound or pharmaceutically acceptable salt thereof, enantiomorph or racemic modification
Figure A0180548900041
Wherein: X and Y represent C1-4 alkyl, C1-4 alkoxyl group, halogen, CF independently 3, OCF 3, CN, C ≡ CH, S (O) mCH 3, S (O) pCF 3, NO 2Or NHCHO; M and p represent integer 0,1 or 2 independently; Z represents hydrogen or fluorine; V represents O; W represents phenyl or contains 1-3 the heteroatomic 5 or 6 yuan of fragrant heterocycles that are independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by one or more halogen, C1-4 alkyl, C1-4 alkoxyl group, OH, CN, NO of being independently selected from 2Or NR 4R 5Substituting group replace; Described alkyl or alkoxyl group can be chosen wantonly by one or more fluorine atoms and replace; R 1And R 2Represent H, C1-4 alkyl or C3-6 cycloalkyl independently; Described alkyl is optional to be replaced by following groups: C1-4 alkoxyl group, halogen, hydroxyl, NR 6R 7, phenyl or contain heteroatomic 5 or 6 yuan of aromatics or the saturated heterocyclic that 1-3 is independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by halogen, C1-4 alkyl, C1-4 alkoxyl group, CF 3, OCF 3, CN or NO 2Replace; Perhaps group NR 1R 2Representative is optional together also comprises one and is selected from O, S or NR 8The saturated nitrogen heterocyclic of other heteroatomic 4-8 unit; Described ring is optional to be replaced by OH or C1-4 alkyl, and described alkyl is by C1-4 alkoxyl group, OH or NR 9R 10Replace; Perhaps group NR 1R 2The part of 5 yuan of aromatics nitrogen heterocyclics that also comprise an other N atom is chosen in representative wantonly together; R 4, R 5, R 6, R 7, R 9And R 10Represent H or C1-4 alkyl independently; R 8Represent H or C1-6 alkyl; Described alkyl is optional to be replaced by following groups: C1-4 alkoxyl group, OH, NR 11R 12, phenyl or contain heteroatomic 5 or 6 yuan of aromatics or the saturated heterocyclic that 1-3 is independently selected from O, S and N; Described phenyl or fragrant heterocycle can be chosen wantonly by halogen, C1-4 alkyl, C1-4 alkoxyl group, CF 3, OCF 3, CN or NO 2Replace; R 11And R 12Represent H or C1-4 alkyl independently; Condition is: when optional phenyl, thienyl, furyl or the pyrryl that replaces of W representative; And R 1Represent H, C1-4 alkyl or C3-6 cycloalkyl, wherein said group is optional when being replaced by the C1-4 alkoxyl group, R 2Do not represent H, C1-4 alkyl or C3-6 cycloalkyl, wherein said group is optional to be replaced by the C1-4 alkoxyl group; With condition be: when W represented thiazolyl or pyridyl, Z represented F; Perhaps have one in the middle of X and the Y at least and represent CN; Perhaps R 1And R 2Dependently represent H or CH 3
21. the formula of claim 20 (Ia) compound, wherein X and Y represent Br, Cl, CH independently 3, CF 3Or CN.
22. the formula of claim 20 (Ia) compound, wherein 1-3 the heteroatomic 5 or 6 yuan of fragrant heterocycles that are independently selected from O, S and N that contain that replace are chosen in the W representative wantonly.
23. the formula of claim 20 (Ia) compound, wherein R 1And R 2Represent H or methyl independently.
24. the formula of claim 20 (Ia) compound, wherein said compound is: 2-[[(3R)-3-(2, the 5-dichlorophenoxy)-3-(2-thienyl) propyl group] amino] ethanol; 4-chloro-2-{[(1R)-and 3-(4-hydroxyl-piperidino)-1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-and the 3-[(2-hydroxyethyl) methylamino]-the 1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-3-[(3R)-3-hydroxyl pyrrolidine base]-the 1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-2-{[(1R)-3-[(3S)-3-hydroxyl pyrrolidine base]-the 1-phenyl propyl] the oxygen base }-benzonitrile; 4-chloro-5-fluoro-2-[3-(methylamino)-1-(2-pyrimidyl) propoxy-] benzonitrile; 4-chloro-5-fluoro-2-((1R)-and the 3-[(3-hydroxypropyl) amino]-the 1-phenyl propyl } the oxygen base) benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 1-(3-furyl)-3-(3-hydroxypropyl) amino] propyl group] the oxygen base } benzonitrile; 4-chloro-5-fluoro-2-{[(1R)-and the 3-[(3-hydroxypropyl) amino]-1-(3-thienyl) propyl group] the oxygen base } benzonitrile; 4-bromo-5-fluoro-2-((1R)-and the 3-[(3-hydroxypropyl) amino]-the 1-phenyl propyl } the oxygen base) benzonitrile; 4-bromo-5-fluoro-2-((1R)-and 1-(3-furyl)-3-[(3-hydroxypropyl) amino] propyl group } the oxygen base) benzonitrile; 4-bromo-5-fluoro-2-{[(1R)-and the 3-[(3-hydroxypropyl) amino]-1-(3-thienyl) propyl group] the oxygen base } benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[(5-methylpyrazine base) methyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[(1H-imidazoles-2-ylmethyl) amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-2-[[(1R)-and 3-[[2-(dimethylamino) ethyl] amino]-the 1-phenyl propyl] the oxygen base]-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(4-morpholinyl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(1H-imidazoles-1-yl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 3-[[2-(1H-imidazol-4 yl) ethyl] amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-the 1-phenyl propyl] the oxygen base] benzonitrile; 2-[[(1R)-and the 3-[(2-amino-ethyl) amino]-the 1-phenyl propyl] the oxygen base]-4-chloro-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[[(1R)-and 1-phenyl-3-[(3,3, the 3-trifluoro propyl) amino] propyl group] the oxygen base] benzonitrile; 2-{[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base }-4-benzyl chloride nitrile; 4-chloro-2-{[(1R)-and 3-(methylamino)-1-(2-thiazolyl) propyl group] the oxygen base } benzonitrile; 2-[3-amino-1-(2-oxazolyl) propoxy-]-4-benzyl chloride nitrile; γ-(2, the 5-dichlorophenoxy)-2-oxazole propylamine; 2-[[3-amino-1-(3-pyridyl) propyl group] the oxygen base]-4-chloro-5-fluorine benzonitrile; 4-chloro-5-fluoro-2-[3-(methylamino)-1-(3-pyridyl) propoxy-] benzonitrile; 2-[3-amino-1-(6-methoxyl group-2-pyridyl) propoxy-]-4-chloro-5-fluorine benzonitrile; 2-[3-amino-1-(1,6-dihydro-6-oxo-2-pyridyl) propoxy-]-4-chloro-5-fluorine benzonitrile; 2-[3-amino-1-(6-bromo-3-pyridyl) propoxy-]-4-benzyl chloride nitrile; 2-[[3-amino-1-(5-isoxazolyl) propyl group] the oxygen base]-4-benzyl chloride nitrile; 4-chloro-2-[3-[(2-hydroxyethyl) amino]-1-(5-isoxazolyl) propoxy-] benzonitrile; (R)-γ-(2, the 5-dichlorophenoxy)-5-isoxazole propylamine; 4-chloro-5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-1-(3-thienyl) propyl group] the oxygen base] benzonitrile; 2-[[(1R)-and the 3-[(2-amino-ethyl) amino]-1-(3-thienyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; 4-chloro-2-[3-(methylamino)-1-(2-thiazolyl) propoxy-]-benzonitrile; 2-[[(1R)-and 3-amino-1-(2-thiazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; 4-chloro-5-fluoro-2-{[(1 R)-and the 3-[(2-fluoro ethyl) amino]-the 1-phenyl propyl] the oxygen base } benzonitrile; 3-[[(3R)-and 3-(2, the 5-dichlorophenoxy)-3-phenyl propyl] amino]-the 1-propyl alcohol; 1-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-the 4-piperidine carbinols; N-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-the 2-thiophene methyl amine; N-[(3R)-3-(2, the 5-dichlorophenoxy)-3-phenyl propyl]-5-methyl-2-furylamine; 5-fluoro-2-[[(1R)-and the 3-[(2-hydroxyethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base]-4-methyl benzonitrile; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-5-fluoro-4-methyl-benzonitrile; 4-chloro-2-[[(1R)-and 3-[(1, the 1-dimethyl ethyl) amino]-1-(3-isoxazolyl) propyl group] the oxygen base] benzonitrile; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-benzonitrile; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; (R)-γ-(2, the 5-dichlorophenoxy)-3-isoxazole propylamine; 2-[[(1R)-and 3-amino-1-(3-isoxazolyl) propyl group] the oxygen base]-4-(trifluoromethyl)-benzonitrile; 2-[[(1R)-and 3-amino-1-(5-methyl-3-isoxazolyl) propyl group] the oxygen base]-4-chloro-5-fluoro-benzonitrile; With their pharmacologically acceptable salt, enantiomorph or racemic modification.
25. as each formula (Ia) compound or its pharmacologically acceptable salt, enantiomorph or racemic modification of the claim 20-24 of medicine.
26. comprise claim 20-24 each formula (Ia) compound or its pharmacologically acceptable salt, enantiomorph or racemic modification and with the pharmaceutical composition of the pharmaceutically acceptable auxiliary of its blended, diluent or carrier.
27. preparation claim 20-24 each formula (Ia) compound or the method for its pharmacologically acceptable salt, enantiomorph or racemic modification, wherein said method comprises: (a) with formula (II) compound
Figure A0180548900081
Wherein X, Y, V and Z react with formula (III) compound as defined in claim 20 Wherein W, R 1And R 2As defined in claim 20; Perhaps (b) is with formula (IV) compound Wherein X, Y and Z as defined in claim 20, and L 1Be leavings group, react with the formula V compound R wherein 1, R 2, V and W as defined in claim 20; Perhaps (c) is with formula (VI) compound
Figure A0180548900093
Wherein X, Y, V, W and Z as defined in claim 20, and L 2Be leavings group, react with formula (VII) compound
HNR 1R 2(VII) R wherein 1And R 2As defined in claim 20; Perhaps (d) is with formula (II) compound
Figure A0180548900094
Wherein X, Y, V and Z react with formula (VIII) compound as defined in claim 20
Figure A0180548900101
R wherein 1, R 2With W as defined in claim 20, and L 3It is leavings group; Perhaps (e) reduces formula (IX) compound
Figure A0180548900102
Wherein X, Y, V, W and Z as defined in claim 20, and G representative changes into NR by proper energy also 1R 2Group; Gained formula (Ia) compound or its another kind of salt can be changed into its pharmacologically acceptable salt when needing; Perhaps gained formula (Ia) compound is changed into other formula (Ia) compound; And gained formula (Ia) compound can be changed into its optically active isomer when needing.
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